Rabbit Anti-Thymocyte Globulin
Rabbit anti-Thymocyte globulin (rATG) is a polyclonal antibody prepared by injection of a rrabit with human lymphoid tissue (thymocytes or activated human T-cell line ); it has largely replaced eATG ( produced from horses ), which is less potent. Mechanism of Action The exact mechanism of action is not fully understood but it contains cyto-toxic antibodies directed against a variety of T-cell markers.
It induce lymphopenia especially T lymphocytes,either by lysis or by removal through reticuloendothelial system.
Of particular importance,Thymoglobulin causes sustained and rapid expansion of CD4+, CD25+, FOXP3+ regulatory T cells that may help in tolerance .its effect may lasts for years . The prolonged immuno-suppressive effect may account for the relative infrequency of
episodes of rejection recurrence.
Dose and Administration
The standard dose of rATG is 1.5 mg/kg given in a course lasting 4 to 10 days.
During induction it is more effective when it is used intra operatively , to reduce the incidence of delayed graft function .
It is given as infusion in 500 ml saline or dextrose given over over 4 to 8 hours into a central vein or arteriovenous fistula.
Patient should be treated by IV premedication consisting of
§ methylprednisolone, 30 mg,given 30 minutes before injection
§ diphenhydramine hydrochloride 50 mg given 30 minutes before injection.
§ Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control.
v Azathioprine, MMF, and sirolimus should generally be discontinued during the course of treatment to avoid exacerbating hematologic side effects.
v Cyclosporine or tacrolimus can be omitted during the course or given in a low dose,
v oral prednisone is replaced by the methylprednisolone given in the premedication.
Adverse Effects
Chills, fever, and arthralgias (common ),
severe first-dose reactions (rare).
Anaphylaxis( occasional) .
Serum sickness (rare). typically presents with diffuse arthralgias, fever, malaise, and rash 1 to 2 weeks following infusion.
Leukopenia occurs in up to half of patients. Which needs dose modification .
The dosed is reduced if leucopenia or thrombocytopenia occur .
If leucopenia occur neupogen can be used .
Absolute lymphocyte count of 0.1% is the target of treatment . Patients who do not respond may require a higher dosage or a prolonged treatment course.
CMV may be a late adverse sequel .its incidence depend on dose and duration of treatment . prophylaxis before, during, and after a course is needed .recipient negative donor positive state is a high risk for CMV infection .
lymphoma is infrequent but a well-recognized complication.Epstein-Barr virus (EBV)negative recipient receiving a graft from an EBV-positive donor appear to be at greatest risk.
Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. it blocks all cytotoxic T cell function. Clinical trials show that muromonab CD3 is effective in reversing acute renal, and combined kidney- pancreas transplant rejection episodes. It also effective in the treatment of rejections resistant to conventional treatment. It is used only when no other option is available .It is more effective than high-dose corticosteroids in reversing first episodes of acute renal. it appears effective as a prophylactic treatment against acute renal rejection in the immediate post-transplantation period. The development of neutralising antibodies may limit the effectiveness of a second course of muromonab CD3 therapy in some patients. PharmacologyMuromonab CD3 is a purified murine monoclonal antibody directed against the CD3 antigen, which is found on all mature human T cells. It is an IgG2a immunoglobulin which binds to one of the subunits of the CD3 complex, a part of the T cell receptor, thereby blocking function of the adjacent Ti complex involved in recognition of foreign antigens by the T cell.Within minutes of intravenous muromonab CD3 administration there is a rapid clearance of CD3+ cells from circulation which is complete within 1 hour. The T cells are believed to be, at least in part, opsonised and removed from circulation by the reticuloendothelial system. muromonab CD3 blocks all T cell function including both the induction and effector phases of cell-mediated lympholysis and T cell proliferative responses to both class I and II major histocompatibility complex antigens.
Mean trough steady-state plasma concentrations of muromonab CD3 are about 0.9 mg/L after about 2 or 3 once-daily intravenous doses of muromonab CD3 5mg. This plasma concentration is generally believed to be adequate to block cytotoxic T cell function based on in vitro studies. Side EffectsThe first doses of muromonab CD3 are associated with a number of side effects which can be frequent and inconvenient or, more rarely, severe and life-threatening. Most side effects occur within 45 to 60 minutes of administration and last several hours .
The most frequent effect is a ‘flu-like’ complex consisting of fever and chills in most patients (> 50%) followed by dyspnoea, tremor, chest pain and tightness, wheezing, diarrhoea, nausea and vomiting in about 10 to 20% of patients, and infrequently tachycardia, hypertension, hypotension, joint pain, pruritus and rash. More severe first-dose effects are aseptic meningitis and pulmonary oedema. Dosage and AdministrationThe recommended adult dose of muromonab CD3 is 5mg administered by intravenous bolus injection once daily for 10 to 14 days. Some patients require as much as 10mg to achieve T cell depletion. Before treatment patients with temperature exceeding 37.8°C should receive antipyretics. T
Intravenous methylprednisolone sodium succinate 1.0 mg/kg given just before muromonab CD3 administration and intravenous hydrocortisone sodium succinate 100mg 30 minutes after muromonab CD3 administration decreases the incidence and severity of first-dose reactions. Paracetamol (acetaminophen) and antihistamines can be given concomitantly with muromonab CD3 to reduce early reactions.
Norman DJ. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20. doi: 10.1097/00007691-199512000-00012. PMID: 8588230
Ahmed Fouad Omar
3 years ago
OKT3(Muromonab CD3,Orthoclone): Mechanism of action:
It is the first approved murine mAb for human use 1986
The biologic target of OKT-3 is the ε chain of CD-3 subunit of the CD3 TCR-associated complex
It initially activates T cells, which leads to a cytokine release syndrome. Then it prevents activation and depletes CD4 and CD8 T cells. Indications:
It is used as an induction agent for high-risk patients.
To treat steroid resistant acute rejection in solid organ transplantation. Side effects:
Cytokine release phenomenon with the first few infusions (due to release of TNF-α and IL-2) characterized by symptoms like headache, nausea, fever, fatigue, myalgia and may lead to life threatening situation(apnea, flash pulmonary edema and cardiac arrest)
Nonspecific T-cell depletion that can result in over-immunosuppression, with increased risk of infections ( bacterial, viral and opportunistic).and PTLD
Neurological side effects (encephalopathy and aseptic meningitis).
Tachyphylaxis was reported with repeated administration
Xenosensitization occurs If repeated doses of OKT-3 treatment are required as the agent is of murine origin and can trigger the production of human anti-mouse antibodies (HAMA) In view of these side effects and the availability of alternative therapies, OKT3 was withdrawn from the market in 2010 Mode of administration:
OKT-3 can be administered through a peripheral vein but it requires filtration before administration of the dose to remove particulate matter in the preparation.
It requires concomitant administration of antihistamines, acetaminophen, and steroids to reduce the incidence of the first-dose response.
It has 100% bioavailability
The usual course of therapy is 7 to 10 days, but is dependent on whether the agent is being used as an induction agent or to treat steroid-resistant rejection.
The adult dose is 3 – 5 mg/kg/day Anti-thymocyte globulin: ATG is a polyclonal IgG-antibody preparation produced by immunizing horses or rabbits with human thymocytes and immunoglobulins against thymocytes are isolated and subjected to a number of purification processes Mechanism of action :
It targets a large variety of immune cell surface proteins, so it does not only deplete T-cells but also down regulates the molecules that control T cell activation. Moreover, it interferes with the function of a number of different immune effector cells, including B cells, dendritic cells, natural killer (NK) T cells, and Tregs
Its efficacy as an immunosuppressive agent is primarily through rapid induced apoptosis of CD3+ T cells. Recovery of peripheral T-cell counts occur gradually after cessation of thymoglobulin treatment (>50% of initial lymphocyte count at 3 months). Indications :
Thymoglobulin is indicated in induction therapy immunologically high-risk patients and those at increased risk of DGF by reducing the ischemia reperfusion injury.
It can be used in TCMR including vascular lesions and as a rescue therapy in steroid resistant acute rejection episodes
ATG is not a first-line treatment for ABMR but might be considered in patients with TCMR-associated acute ABMR Side effects :
1. Anaphylaxis, with a drop in blood pressure, respiratory distress, fever and urticaria may appear during or just after the infusion. Other hypersensitivity reactions include rigors, arthralgia, erythema and pruritic skin eruptions
2. Increase risk of infections especially CMV and PTLD
3. Other side effects include thrombocytopenia ,neutropenia and serum sickness Mode of administration and dosage :
Infused through a central line but can also be given in peripheral line.
To reduce severity of infusion related reactions, pre-medicate with corticosteroids, acetaminophen, and antihistamines 1 hour prior to infusion and give the first dose over at least 6 hours; subsequent doses may be infused over at least 4 hours.
Start prophylaxis against antifungal infection(nystatin), Pneumocystis jiroveci infection(Co-trimoxazole) for 3 months and CVM infection with (valgancyclovir) for 6-12 months
Induction doses have ranged from 1–6/kg/dose over 1–10 days with a more typical regimen of 1.5 mg/kg for 3–5 days starting from day zero.
For acute rejection ATG is given at dose of 1.5 mg/kg/day IV for 7-14 days References
1.Sgro, C. (1995-12-20). “Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review”. Toxicology. Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology. 105 (1): 23–29
2.Simon steddon,Neil Ashman. Handbook of Nephrology and Hypertension. second addition
AMAL Anan
3 years ago
OKT3-(Muromonab-CD3):
Monoclonal antibody acts against CD3 receptor which On T Lymphocytes.
The Side effects of Muromonab-CD3 is variable which includes pulmonary oedema, gastrointestinal and neurological abnormalities (7). The feedback of use Murmonab-CD3 as induction therapy among transplant recipient
There is distrust about its uses and effects on kidney transplantation
It is found that the use of the OKT3 is masked by other immunosuppressive agents .
Recently it was withdrawn from the US markets(7).
Antithymocyte globulin
Polyclonal antibody which has 2 forms either rabbits (rATG) or horses (ATGAM) .
Its action is not appear clear but it lysis the complement of various immunocompetent of the cell .
The immune system took time to recover especially in old ages (8).
The side effects of Antithymocyte globulin
Sever first dose reaction ( cytokine release syndrome):chills, fever arthralgia and hypotension
Thrombophlebitis and peripheral vein thrombosis Thrombocytopenia and leukopenia Developing infection especially cytomegalovirus
Anaphylaxis Post-transplantation lymphoproliferative disease(PTLD)
Mohammed Sobair
3 years ago
OKT3 blocks both the generation and function of cytotoxic T cells. After an initial dose
of OKT3, T cells virtually disappear from the circulation within minutes to hours. During
treatment with OKT3, T cells .
OkT 3 used to treat rejection.
Side effect associate associate. With cytokine release .Increase risk of infection.
ATG used in induction therapy and treatment of rejection..
References :
DJ Norman .Mechanisms of action and overview of OKT3. Drug Monit. 1995
Dec;17(6):615-20.
Ramy Elshahat
3 years ago
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action
ATG is depleting polyclonal antibodies: polyclonal means multiple b cell colonies are involved in its formation as multiple antigens are used (cd2,3,4,8,18)and injected in animal (rabbit and horse) during its manufacture
ATG cause both bcell and Tcell depletion
Okt3 is monoclonal antibodies:single colony of b cell is involved in its manufacture as single antigen is used cd3 causing only tcell depletion
According to indication
ATG: Is used in 1) induction therapy: used preoperative or intraoperative in moderate to high risk patient with dose around 3mg/kg in divided doses
2) used in treatment of both tcell mediated rejection (when resistant to steroids or score 2a or more) or ABMR or mixed rejection in dosing 5-9mg/kg
Okt3:the original use was for treatment rejection but it was used in some pediatric centers for induction
According to side effect
ATG: causes serum sickness, cytokines release syndrome, anaphylaxis reaction, pancytopenia, increase risk of infection specially CMV virus and PNC bacterial infection and increase risk of PTLD
OKT3: cytokines storm, anaphylaxis shock, CMV infection and PTLD
Regarding mode of administration?
ATG : used as infusion over 6h in large veins proceeded by methylprednisolone and acetaminophen if mild reaction happened it can hold then continue on slow rate but if sever reaction happened it should be discontinued.also cbc showed be followed
If plt count below 50000 or TLC below 2000 next dose should be held but if plt count ()75000 and 50000 or TLC ()3000 and 2000 next dose should be halved
Okt3: it given as a bolus so its can’t withdrawal or decreasing infusion rate as ATG
REFERANCES
1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-203
2. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
3. Kutzler HL, Ye X, Rochon C, Martin ST. Administration of antithymocyte globulin (rabbit) to treat a severe, mixed rejection episode in a pregnant renal transplant recipient. Pharmacotherapy. 2016;36(4):e18‐e22.
4. Adair JC, Woodley SL, O’Connell JB, et al. Aseptic Meningitis following Cardiac Transplantation: Clinical Characteristics and Relationship to Immunosuppressive Regimen. NeuChatenoud L, Legendre C, Ferran C, et al. Corticosteroid Inhibition of the OKT3 – Induced Cytokine-Related Syndrome – Dosage and Kinetics Prerequisites. Transplantation 51:334–338, 1991.
5. Cockfield SM, Preiksaitis J, Harvey E, Jones C, Herbert D, Keown P, and Halloran PF, et al. Is Sequential Use of ALG and OKT3 in Renal Transplants Associated with an Increased Incidence of Fulminant Post Transplant Lymphoproliferative Disorders? Transplant. Proc. 23:1106–1107, 1991.rology 41:249–252, 1991.
Amit Sharma
3 years ago
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action, indication, side effect and mode of administration? Mechanism of action:
OKT3: Muromonab or OKT3 is a an anti CD3 monoclonal antibody. It is directed against the e subunit of CD3 closely associated with T cell receptor on T cell, binding to the T cell and leading to complement activation with T cell apoptosis.
Thymoglobulin: It is rabbit Anti Thymocyte Globulin (rATG), a purified polyclonal antibody. It mainly targets the pre-activated, non-cycling memory lymphocytes. Its main action is T lymphocyte depletion by complement dependent cell lysis. It also binds with B cell surface proteins including CD30, CD38, CD80 and CD95 leading to apoptosis and depletion of B cells.
Indication: In transplantation
OKT3: OKT3 has been used as:
1) Treatment of acute rejection
2) Prevention of acute rejection: Induction therapy
In non-transplant setting, OKT3 has been used in T cell Acute lymphocytic Leukemia
Thymoglobulin: It has been used as:
1) Prevention of acute rejection: Induction therapy for high immunological risk patients.
2) Treatment of acute rejection: For acute T cell mediated rejection or mixed rejections.
Side effect: The side-effects are:
OKT3:
1) Cytokine release phenomenon: This happens due to initial activation of T cells releasing TNF alfa and interleukin 2. It presents with headache, nausea, fever, fatigue, body-aches, shortness of breath, pulmonary edema or cardiac arrest.
2) Non-specific T cell depletion: Leading to over-immunosuppression, increased risk of infections and PTLD.
3) Leukopenia
4) Neurological: Encephalopathy, aseptic meningitis, cerebral edema.
5) Tachyphylaxis: with repeated doses
6) Anaphylactic reactions.
Thymoglobulin:
1) Cytokine release phenomenon: This happens due to initial activation of T cells releasing TNF alfa and interleukin 2. It presents with headache, nausea, fever, fatigue, body-aches, shortness of breath, pulmonary edema or cardiac arrest. 2) Leukopenia, Thrombocytopenia 3) Abdominal pain, nausea 4) Infections: UTI, CMV 5) PTLD 6) High blood pressure or hypotension 7) hyperkalemia
Mode of administration:
OKT3: The dose of OKT3 is 5 mg/kg/day intravenous fast over less than one minute. for 7-10 days. It can be administered via a peripheral vein. Premedication with IV methylprednisolone, paracetamol and anti-histamines is warranted to decrease the incidence and severity of first dose reactions.
Thymoglobulin: Dose is 1.5 mg/kg/day for 4-7 days as induction therapy and 7-10 as treatment for rejection. It is administered as IV infusion over 4-6 hours through a central line after premedication with IV methylprednisolone, paracetamol and anti-histamines to prevent infusion related reactions.
Which one you prefer to give?
We use rATG (Thymoglobulin). OKT3 is not available. Even if OKT3 were available, rATG has a better safety-profile than OKT3 and hence better to use.
Mahmoud Hamada
3 years ago
OKT3: mechanism of action:Bind to TCR-CD3 , leading to clearance of TCR and hence T cell apoptosis.
indication
Acute sterid rejection kidney transplantation side effect
Infusion reactions, chills, urticaria, flash pulmonary edema. mode of administration
Intravenous infusion
Thymoglobulin::mechanism of action:polyclonal antibody acting on several site including b and t cells, natural killer cell but mainly act though CD3 t cell depletion indication
not only treatment of rejection as okt3 , but also may be used for prevention of such rejection. side effect
hypo- and hypertension , tachycardia, abdominal pain, constipation, Acne mode of administration
1st dose: iv infusion over 6 hours
other dosed Iv infusion over 4 hours.
Ahmed Omran
3 years ago
OKT3 is a monoclonal AB which inhibits signal 1through its action against CD3,ATG is polyclonal AB ;a lymphocyte depleting agent.
OKT3 was used in treatment and prevention of acute transplant rejection ;withdrawn from market.
Side effects of OKT3 : some include cytokine syndrome ,leucopenia and CNS side effects.
ATG
lymphocyte depleting through complement dependent cell lysis.
used as induction therapy in addition to conventional immunosuppression specially in high risk patients.
Some of its side effects include increased infection &malignancy ,allergic and hematological side effects.
ATG is the currently used agent
Mohamed Essmat
3 years ago
rThymoglobulin ( rabbit ATG ) . Is a polyclonal antibody , It has replaced equine ATG . The exact mechanism of action of ATG is not fully understood but it is believed to be directed against various T cell markers leading to cell lysis. Uses : As induction therapy
Treatment of steroid resistant cellular rejection Usual dose is 1.5 mg /kg for 4 to 10 days Side effects include: Hypersensitivity reactions Leukopenia and thrombocytopenia Infections Lymphoma OKT3 is a monoclonal antibody directed against CD3 ,which is a molecule found only on mature T cells . CD3 is located very near to TCR for antigens ,OKT3 blocks both the generation and function of cytotoxic T cells.The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3 OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. It’s only given through IV route. Adverse effects include: *Serious anaphylaxis * cytokine release syndrome * Aseptic meningitis and encephalopathy have been observed. We use ATG , No OKT3
Nasrin Esfandiar
3 years ago
OKT3 act as a monoclonal antibody against CD3 and inhibits signal one. Thymoglobulin is a polyclonal antibody which is provided by immunization of rabbits with human lymphoid tissue and thymocytes are used for it. OKT3 had potent life-threatening first- dose reactions such as chills and fever and respiratory symptoms caused by inflammatory mediators. Nowadays it is replaced by thymoglobulin. Thymoglobulin contains antibody against different kinds of T cell markers and causes depletion of peripheral lymphocytes and can cause prolonged lymphopenia .It is used for induction of immunosuppression and treatment of refractory T cell rejection. Other side effects is chills and fever with lower intensity than OKT3 .To prevent its reaction side effects, premedication with acetaminophen, antihistamines and corticosteroid is considered. Other side effects include serum sickness, thrombocytopenia and leukopenia which need dose reduction or sometimes stopping the drug. CMV infection is a well-known side effect that necessitated CMV prophylaxis while they are administrated. OKT3 was administer by IV bolus infusion. Recently oral administration of humanized anti-CD3 monoclonal Ab is used for treatment of non- alcoholic steatohepatitis (NASH) .Thymoglobulin is administered by IV route. Initially it was recommended by central line but recently peripheral IV administration was shown to be safe by using premedication over 6 hours.
Asmaa Khudhur
3 years ago
OKT3
Mechanism of action :
When administered, OKT3 cause rapid activation and cytokines release from all CD3+cells
Subsequent internalization of the T-cell receptor and T-cell unresponsiveness.
Clearance of >90% of CD3 cells from the circulation within 24 hours
Indication:
as induction therapy in renal transplantation and in the treatment of acute rejection.
Adverse effects:
Anaphylaxis
Cytokine release syndrome
Increase infections
Increase in post-transplant PTLD
Administration of OKT3:
Premedication (IV methyl prednisolone,IV H1 antagonist ,paracetamol PO)
Dose:
given as an IV bolus of 5 mg (2.5 mg for children <30 kg ) into peripheral vein .
give daily for 10 days.
Thymoglobulin:
Mechanism of action
ATG administration has multiple effects including T-cell activation,leading to cytokines release , clearance of T cells from the circulation,inhibition of both co-stimulatory and proliferative signals and inhibition of cell adhesion and migration.
Indication:
Used in induction therapy for renal transplantation and for acute kidney rejection.
Adverse effects:
Anaphylaxis
Cytokine release
Decrease WBC and platelet
Increase infections
Increase in PTLD
Serum sickness
Administration of ATG :
Test dose:
5 mg in 100 ml 0.9%NaCl over 30 minutes into a peripheral vein is given without premedication.
Thymoglobulin is usually diluted into 500 ml 0.9 NaCl (the final concentration should be 6 hours (first dose ) or > 4 hours ( subsequent doses)
ATG mostly used due to its less side effects
OKT3 removed from the market
Ben Lomatayo
3 years ago
OKT3 vs Thymoblobulin :
Mechanism of action ; Both are lymphocytes depleting agents. ATG is polyclonal T cell depleting agent produced by immunising Rabbits with human thymic lymphocytes. OKT3 is mouse mAb specific for CD3
Indication ;Both are used as induction therapy and for treatment of rejection. however OKT3 less use these days due to more side effects
Side effects ; Both are associated with ;
Anaphylaxis & cytokine release syndrome;
High risk of infections e.g. PCV,CMV HSV
High risk of PTLD
Cytopenia’s
Mode of administration ; They are given IV through central line. OKT3 can be given peripherally.
Oxford hand book of nephrology & hypertension ,second edition.
Tahani Hadi
3 years ago
Thymoglobulins are anti lymphocyte polyclonal Ab produced by activating the immune system of either rabbit or horse by human lymphoid tissue.
OkT 3 orthoclone is a monoclonal Ab muromonab-CD3.
Mechanism of action of thymoglobulins:
Contains cytotoxic Ab directed against T cells causing decrease in their number in peripheral blood by T cells lyses by reticuloendothelial system and masked their surface Ag .
Thymoglobulin also cause expansion of FOXP3+ regulatory T cells which plays crucial role in immune response balance and decrease risk of graft rejection and loss it causes prolonged lymphopenia and CD4 inhibition which may prolonged to several years thus help preventing rejection episodes.
Administration:
1.5 mg /kg dose diluted in 500ccN/S or dextrose within 4-8 hrs in large central veins to avoid it’s thrombophlebitic effects, vital signs should be monitored regularly and closely,premedications should be given prior to thymoglobulins administration to decrease side effects.
Side effects:
Mainly due to administration of foreign protein causing anaphylaxis like reaction like chills,fever,generalised weakness,rash and may continue over 1-2 week after the dose ,this effect can be minimized by using pre medications before treatment like acetaminophen, methylprednisolone ,diphenhydramine and hydrocortisone.
Blood count monitoring is necessary because it’s leukopenic effect which needs to reduce to half dose or stop the infusion and if it’s sever neupogen may be used .
OKT 3 muromonab CD3
Is the first monoclonal Ab that had been used in clinical practice as human immunosuppressant by it’s effects on CD3 receptors on T cells surface used for acute cellular rejection ,it’s IgG 29 Ab binds to TCR ,CD3 complex leading to T cells apoptosis and prevent graft rejection .
Administration
The dosage of OKT3 is 5mg/day in bolus IV injection can be given on peripheral veins for less than 1 minute for 10-14 days ,premedications also must be given to decrease or prevent drug side effects.
Side effects
After administration of OKT 3 this will release cytokines like TNF and interferon gamma which are responsible for it’s side effects that are known as (cytokines release syndrom) like skin reaction fatigue, fever,rigor GI symptoms,and even life threatening conditions like pulmonary oedema apnea and even cardiac arrest ,these all can be avoided by using acetaminophen, methylprednisolone and diphenhydramine as pre medications. Other side effect is leukopenia and this will increase risk of infection ,aseptic meningitis encephalopathy and malignancies..
Both these drugs are used to prevent acute cellular rejection so they can be used in induction and in treatment of cellular rejection.
Thymoglobulins can be given also in AMR due its effect on CD4+T cells and B cells interaction so it cause B cells apoptosis and AlloAb production modulation so it cause decrease B Cells but it’s action tends to be more effective when it used with rituximab (not used thymoglobulins as monotherapy in AMR patients).
Fatima AlTaher
3 years ago
1- OKT3
a- Mechanism of action :
Monoclonal Ab ,Blocks CD3 function in T lymphocytes , required for Ag recognition & signal transduction)
b- Indications :Treatment of acute kidney allograft rejection
4- Complications related to immunesuppression effects as increase risk of infections and malignancy.
d- administration
1- Premedication with 1 mg /Kg methyl prednisolone
2- Filter OKT3 with a low protein-binding 0.22 micron filter
3- Then administer OKT3 as IV push undiluted Followed by hydrocortisone 50 – 100 mg Iv .
ATG a- Mechanism of action : Polyclonal Ab with
1- cytotoxic effect against a variety of T-cell markers leading to depletion of prepheral lymphoctyes
2- causes rapid sustained expansion of CD4+, CD25+, FOXP3 T reg cells involved in graft tolerance.
b- Indications :
1- Induction therapy for high risk patients
2- Treatment of acute graft rejection
c- S.E:
Same as OKT3
1- Hematological effects as leukopenia (including lymphopenia and neutropenia) , thrombocytopenia.
d- administration a;
1- Premedicate recommended with corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion.
2- Slow infusion over 4-6 h diluted in either 0.9 normal saline or 5% dextrose. Each vial should be diluted in 50 mL of infusion solution
3- Infuse IV through 0.22 micron filter into high-flow vein.
4- Decrease the dose by 50% if WBC is ≥2000 but ≤3000/mm3 or platelet count is ≥50,000 but ≤75,000/m3. Consider drug discontinuance if WBC <2000/mm3 or platelet count <50,000/mm3.
MICHAEL Farag
3 years ago
OKT 3 OKT3 is a murine monoclonal antibody of the immunoglobulin IgG2a isotype. The target of OKT3, CD3, that is part of a multimolecular complex found only on mature T cells and medullary thymocytes. This complex is uniquely situated next to the T-cell receptor for antigen. An interaction between T cells, OKT3, and monocytes causes T-cell activation Because of the unique association between the antigen receptor and CD3, antibodies that react with CD3 block T-cell receptor function and vice versa. Thus, OKT3 blocks both the generation and function of cytotoxic T cells. Indication
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. Orthoclone OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. Side effects Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines ; cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea, and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.[7] To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion. Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation. Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, which may be difficult to distinguish from a CRS. Mode of Administration Give IV push over <1 min undiluted Do not give IM Methylprednisolone sodium succinate 1 mg/kg IV given prior to first muromonab-CD3 administration, & IV hydrocortisone sodium succinate 50-100 mg, given 30 min after administration are strongly recommended to decrease the incidence of reaction to the first dose Filter each dose through a low protein-binding 0.22 micron filter before administration Pt temperature should not exceed 37.8°C (100°F) at time of administration antithymocyte globulin Polyclonal antibodies against human lymphoid tissue. Currently, two ATG preparations are available. Antithymocyte globulin equine (eATG) is a purified, concentrated and sterilized antibody preparation derived from the hyperimmune serum of horses. Antithymocyte globulin rabbit (rATG) is also a cytolytic polyclonal antibody preparation . It is a purified and pasteurized preparation of gamma immunoglobulin obtained by immunizing rabbits with human thymocytes. Equine ATG contains antibodies against several T-cell surface markers and after binding to these markers, eATG promotes T-cell depletion by either opsonization and complement-mediated lysis or clearance into the reticuloendothelial system. Cell recovery after depletion with eATG may take several months. Overall, this agent reduces the number of lymphocytes in the peripheral circulation, as well as in the thymus and spleen. rATG induces immunosuppression in vivo include T-cell clearance from the circulation and modulation of T-cell activation, homing and cytotoxic activities. In vitro, rATG mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. rATG is thought to induce T-cell depletion and modulation by a variety of methods, including Fc receptor-mediated complement-dependent lysis, opsonization and phagocytosis by macrophages, and immunomodulation leading to long-term depletion via apoptosis and antibodydependent cell-mediated cytotoxicity. Immune reconstitution may take several months following a course of rATG. Indications – the prophylaxis and treatment of acute rejection in patients receiving a kidney transplant in conjunction with concomitant immunosuppression – Aplastic Anemia – Myelodysplastic Syndrome – prevention of graft vs host disease Side effects Abdominal pain and other GI symptoms, Asthenia, Chills, Diarrhea, Dyspnea, Fever Headache, HTN, Hyperkalemia, Infection, Leukopenia, Malaise, Peripheral edema, Tachycardia, Thrombocytopenia (37%) Administration
The standard induction therapy dosing strategy for eATG is 10–30 mg/kg/day IV for 7–14 days. The first dose usually begins shortly before or after transplantation. However, the difficult outpatient administration and high cost of this agent make this prolonged course difficult in many instances. A shorter course of therapy is often used to counter these issues and consists of dosing eATG at 15 mg/kg/day for 7–10 days, stopping once the maintenance immunosuppressive regimen is optimized
Rabbit ATG is not FDA approved for induction therapy; however, many in the transplant community routinely use this antibody for induction therapy. When used in this capacity, rATG has been dosed at 1–4 mg/kg/day and is usually administered for 3–10 days after transplantation. The most common dosing schedule for this agent is four doses of 1.5 mg/kg/day, resulting in a total dosage of 6 mg/kg over the course of the therapy
IV Preparation
Aseptically reconstitute required number of vials with 5 mL supplied diluent (SWI) immediately before use Gently rotate vials to dissolve particulate matters if any; discard if particulate matters persist
Transfer all reconstituted drug into infusion bag containing saline or dextrose, invert bag to mix
Recommended volume: 50 mL of infusion solution per vial (total volume between 50-500 mL)
Premedicate recommended with corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion; may reduce the incidence and intensity of infusion-associated reactions
Infuse IV through 0.22 micron filter into high-flow vein Infuse first dose over at least 6 hr and subsequent doses over at least 4 hr
Nazik Mahmoud
3 years ago
OkT3 is a monoclonal antibody specific for CD3 antigen which expressed in all T cells, administered as IV bolus of 5 mg daily for 10 days,has very rapid action within one hour by activation and release of cytokines from CD3 cells; clearance of more than 90% of CD3 within 24 hours. Adverse effect include anaphylaxis and cytokine release syndrome.
Antithymocyte globulin is apolyclonal T cell depleting antibodies,it works against of CD3,CD4 and CD8. The mechanism of action by T cell activation, cytokine release, clearance of T cells from circulation,inhibition of both co stimulatory and proliferative signals,it have some activity to suppress B-cell and plasma cell. Mode of Administration is IV of dose 1.5mg /kg for 4 days (total dose of 6mg),first dose start intraoperative .side effects is cytokine release syndrome , serum sickness and long standing lymphocytes depletion for 6 months .
ATG is preferred than OKT3 due it is less side effects and potent action
Professor Ahmed Halawa
Admin
3 years ago
Dear All Is any one of you still using OKT3 in his centre? Feel free to say yes or no. It is just a screening question
it is an old monoclinal antibody, was used in induction therapy as t-cell depleting therapy and also in acute rejection.
it works by blocking CD3 surface marker on T-lymphocytes, resulting in deactivation and depletion of T-lymphocytes.
side effects are serious due to excessive cytokine release and include systemic reactions as fever, chills, bodyaches, fever, encephalopathy, pulmonary edema …… may be life-threatening.
it is used as 5 mg IV bolus od for 10-14 days.
ATG :
they are polyclonal antibodies, directed against a variety of T-cell markers, resulting in depletion of T-lymphocytes.
they are used in induction therapy and also in acute rejection.
the dose is 1.5 mg/kg IV for 4-7 days
side effects are better than OKT3. they include less systemic reactions, thrombocytopenia, leukopenia, infections as CMV, development of B-cell lymphoma.
Alyaa Ali
3 years ago
Thymoglobulin Mechanism of action :
it is polyclonal antibodies contain cytotoxic antibodies directed against a variety of T cell markers lead to depletion of peripheral blood lymphocytes
causes sustained and rapid expansion of CD4+,CD25+,FOXP3+ regulatory T cells that play an important role in maintaining immune homeostasis and limiting antigraft immunity. Indication:
used for induction therapy prevent and treat acute rejection and increase graft survival in solid organ transplantation , especially kidney, liver, pancreas, and heart transplantation. Mode of administration: dose 1.5 mg/kg given in course lasting 4 to 10 days intravenous infusion in 500 ml dextrose or saline over 4 to 8 hours with intravenous premedication 30 minute before injection by methylprednisolone 30 mg. Side effects: Chills,fever and arthralgia , occasional cases of anaphylaxis thrombocytopenia , leukopenia with the need of reduction or stopping of drug infection : CMV very common using repeated courses of the drug is associated with fulminant and rapidly fatal B cell lymphoma OKT3 Mechanism of action:
it is lymphocyte depleting monoclonal antibody react with human T cells by binding to one of the 20-KDa subunits of the CD3 complex ( the intrinsic part of the T cell receptor )
with deactivation of the CD3 complex and endocytosis of T cell receptor after that T cell will removed from circulation
Depletion of T cells with surface markers CD4,CD8,CD11
Block function of killer T cells Indication:
induction therapy but because life threatening first dose reaction it replaced by less toxic thymoglobulin ( similar effect)
used when thymoglobulin is contraindicated due to leukopenia or thrombocytopenia Mode of administration:
5 mg intravenous bolus through Millipore filter daily for 10 days Side effects ; infection and lymphoma risk are similar to thymoglobulin severe life threatening adverse reactions may occur during the first days of administration rapidly developing life threatening noncardiogenic pulmonary edema if the patient over his dry weight neurological complication varying from mild headache to severe encephalopathy References Handbook of Kidney Transplantation . Fifth Edition
Wessam Moustafa
3 years ago
Okt3
Is monoclonal antibody, of IgG isotype, directed against CD3 ,which is a molecule found only on mature T cells and thymocytes .
CD3 is located very near to TCR for antigens , it was found that any antibody that blocks CD3 ,precent T cells from interactions with antigens
OKT3 blocks both the generation and function of cytotoxic T cells.
The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3
OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients.
Is only given through IV route .
Orthoclone OKT3 should not be given to patients who:
are hypersensitive to this or any other product of murine origin.
have anti-mouse antibody titers ≥1:1000.
are in (uncompensated) heart failure or in fluid overload, as evidenced by chest X-ray or a greater than 3 percent weight gain within the week prior to planned Orthoclone OKT3 administration.
uncontrolled hypertension.
history of seizures, or are predisposed to seizures.
pregnant, or who are breast-feeding.
Adverse effects include
*Serious anaphylaxis which may be life threatening
* clinical release syndrome
*Neurological side effects like aseptic meningitis and encephalopathy have been observed.
Thymoglobulin ( rabbit ATG ) .
Is a polyclonal antibody, produced by injecting rabbits with human thymocytes inducing immune response, and obtained rabbit s serum to get the Immunoglobulins .
It has replaced equine ATG .
Exact mechanism of action of ATG is not fully understood but it is believed to be directed against various T cell markers leading to cell lysis .
It also causes expansion of CD4 , CD25 foxp3 and regulatory T cells which plays an important role in managing rejections .
Uses :
As induction therapy
Treatment of steroid resistant cellular rejection
Usual dose is 1.5 mg /kg for 4 to 10 days
Side effects include
Sever 1st dose reactions
Leukopenia and thrombocytopenia
Infections including cmv
Lymphoma
Given on 500 ml dextrose 5 % , over 4 to 8 hours ,
Pre medications as antihistamines, paracetamol, hydrocortisone should be given
Handbook of clinical transplantation
Gabriel M.Danovitch
Mahmud Islam
3 years ago
OKT3 which is a murine monoclonal antibody of immunoglobulin IgG2 isotype targets CD3. It blocks both generation and functşon of cytotoxic T cells. It is not widely used because of side effects and the formation of anti-OKT3 antibodies. It has a high incidence of first use side effects related to cytokine storm manifested as fever and chills etc.
On the other hand, thyroglobulin is safer somehow
It has different formulations like höse or rabbet derived. The most widely used is rATG (rabbit ATG).
ATG is thought to have an effect on T, B, and plasma cells. It depletes T cells within a short time by complement-dependent cell lysis. T cell modulation is another probable mechanism of action.
— Treatment with rATG down-modulates the expression of several molecules that control T-cell activation, including the T-cell receptor (TCR)/CD3 complex, CD2, CD4, CD5, CD6, and CD8
— rATG contains antibodies that can bind syndecan (CD138), a plasma-cell-specific molecule
— . rATG is thought to bind with numerous B-cell surface proteins like CD30, CD38, CD95, CD80, and HLA-DR
Both are indicated for transplant immunosuppression induction as well as acute rejection
ATG is a mixture of non-specific anti-lymphocyte immunoglobulins targeting not only T cell subsets but also several other immune and non-immune cells.
It has the capacity to deplete T and B cells, to inhibit B and T cell cooperation as well as leucocyte adhesion and to induce certain ‘tolerogenic’ regulatory T cell and dendritic cell (DC) populations.
addition to T-cell depletion, ATG may also result in less T cell activation by the downregulation of molecules that control T cell activation, such as the TCR/CD3 complex, CD2, CD4, CD5, CD6 and CD8.
ATG could act on leucocyte adhesion through downregulation of the cell surface expression of several integrins and intercellular adhesion molecules (e.g. ICAM-1, VCAM, PECAM, CD11b and CD62e) .
MECHANISM OF ACTION OF ATG
ATG is polyclonal immunoglobulin G (IgG) fractions purified from sera of rabbits or horses previously immunized with human lymphocytes.
The sources of lymphocytes are human spleen, blood, thymus or lymphoblastic lineages. After purification, polyclonal cytotoxic antibodies are isolated and able to target numerous immune cell clusters of differentiation and membranous antigens (e.g. CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA type I etc.).
After infusion, ATG induces immediate immune cell depletion, particularly T lymphocyte depletion, through four known mechanisms :
1 The antibody-dependent cell cytotoxicity pathway is the main mechanism and is the consequence of fixation of the polyclonal antibodies on its specific antigens, while the Fc part of the antibodies are recruiting Fcγ receptor cytotoxic cells [macrophages and natural killer (NK) cells].
2The complement-dependent cell cytotoxicity is dose dependent and related only to those antibodies that are able to fix complement C1q with their Fc part.
3 The opsonization process involves phagocytosis of antibody-recovered T lymphocytes by the reticulo-endothelial network.
4 The activation-induced cell death pathway occurs through the antibody-induced and cytokine-mediated upregulation of CD178 (CD95-L) expression by resting T cells. The Fas-Fas ligand pathway activation induces T lymphocytes apoptosis.
INDICATIONS FOR ATG
1 ATG as prophylactic induction therapy in solid organ transplantation
Induction results in initially lower graft rejection rates , allowing early steroid withdrawal and hospital discharge.
Eventually, ‘mild’ rejections, which are easy to treat, and steroid-resistant rejections in highly immunized patients are prevented, while rejections with inferior outcomes such as humoral rejections are less well prevented,
2 Treatment of acute TCMR
In meta analysis puplished 2006 monoclonal and polyclonal antibody therapy were better than steroids in reversing ongoing rejection and preventing graft loss whether death-censored or including death with a functioning graft . There was no difference in preventing subsequent rejection at 1 year.
ATG has been used as a first-line therapy for TCMR, in particular, those with severe acute TCMR including vascular lesions (≥Banff II categories) and as rescue therapy for steroid-resistant acute TCMR.
Current KDIGO guidelines recommend corticosteroids for the initial treatment of acute cellular rejection (1D) and suggest adding or restoring maintenance prednisone in patients not on steroids who have a rejection episode (2D) .
3 Steroid-resistant acute rejection
evidence-based data are scarce, old and do not allow using ATG as a first-line therapy in mild to moderate first acute rejection. Current KDIGO guidelines suggest using lymphocyte-depleting antibodies or OKT3 for acute cellular rejections that do not respond to corticosteroids and for recurrent acute cellular rejections (2C).
4 Acute ABMR
One retrospective study has evaluated seven high immunological risk patients who developed early post-transplant acute ABMR [60]. The treatment consisted of an ATG-based regimen (mean dose 0.79 mg/kg/day for a median of 6 days), including steroid pulse therapy and plasma exchange. The authors showed a significant decrease in post-treatment creatinine with an improvement in graft function in six of the seven patients with this multimodal treatment. In general, until now we have had no data indicating that patients treated prophylactically with ATG induction experienced less ABMR or donor-specific antibodies.
ATG can act on B cells and plasma cells through direct or indirect pathways. Most studies evaluating ATG in the treatment strategy of ABMR are particularly reported in mixed rejection
Side effects
1 ATG is associated with higher risk of opportunistic infections and cancerespecially post-transplant lymphoproliferative disease .
2 negative impact of ATG-induced serum sickness disease (SSD) on allograft survival has reopened the debate on the intrinsic toxicity of this powerful immunosuppressant
3 ATG infusion may cause a cytokine release but less than OKT3.,
4 there were fever, chills and malaise following antibody administration.
Before administration CBC must be done to ensure no infection, ↓platelets or ↓WCC
• patient must be euvolemic not overloaded
, dialysis for patients with AR pulmonary oedema.
one hour before the dose of Thymoglobulin give:
• IV hydrocortisone 100mg
• IV H antagonist.
• PO paracetamol 1000mg
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be 6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
OKT3
is monoclonal antibody against CD3 . it’s administration leads to depletion of T cells it use has stopped .
It blocks the function of T cells and blocks the function of a molecule called CD3 in the membrane of T cell.
indicated for the treatment of acute allograft rejection in renal transplant patients.
Side effects
first doses of muromonab CD3 may be associated with cytokine-release syndrome as it activate T cells to release cytokines like tumor necrosis factor and interferon gamma.
This cytokine release syndrome, appears as skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea and could lead to life-threatening conditions like : apnoea, cardiac arrest, and flash pulmonary edema
Also it causes leucopenia, increased risk for severe infections and malignancies.
Reference
1 Couvrat-Desvergnes G , Salama A , Le Berre L et al. Rabbit antithymocyte globulin-induced serum sickness disease and human kidney graft survival. J Clin Invest 2015; 125: 4655–4665.
2 Jamal Bamoulid, Oliver Staeck, Thomas Crépinet al .Anti-thymocyte globulins in kidney
transplantation: focus on current indications and long-term immunological side effects
.Nephrology Dialysis Transplantation, Volume 32, Issue 10, October 2017, Pages 1601–1608,
Mina Meshreky
3 years ago
____Mechanism of action____
●OKT3 was the first monoclonal antibody used to treat patients.
OKT3 acts by blocking the function of T cells which play a major role in acute graft rejection.
OKT3 reacts with and blocks the function of a molecule called CD3 in the membrane of T cell.
OKT3 is a
—->murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells blocks T cell function.
A rapid decrease in T lymphocytes occurs within a few minutes after administration of muromonab CD3.
This antibody is used mainly for the treatment of acute organ transplant rejection.
●Antithymocyte globulin (rabbit) is a polyclonal antibody which appears to cause immunosuppression by acting on T-cell surface antigens and depleting CD4 lymphocytes
________ INDICATIONS________
1- OKT3
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. Orthoclone OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients.
●ATG INDICATIONS
1-Renal transplant (acute rejection treatment): IV: 1.5 mg/kg/day for 7 to 14 days
2-Renal transplant (induction therapy): IV: 1.5 mg/kg/day for 4 to 7 days; the first dose should be administered prior to reperfusion of the donor kidney.
_________SIDE EFFECTS_______
OKT3
The first doses of muromonab CD3 are associated with a flu-like “cytokine-release syndrome includes
binding of muromonab-CD3 to CD3 that can activate T cells to release cytokines like tumor necrosis factor and interferon gamma.
This cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea and could lead to life-threatening conditions like : apnoea, cardiac arrest, and flash pulmonary edema.
To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone),
acetaminophen, and diphenhydramine are given before the infusion.
Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies.
Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation.
Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti mouse antibodies in the patient which accelerates elimination of the drug.
It can also lead to an anaphylactic reaction against the mouse protein which may be difficult to distinguish from a CRS.
●ATG
☆Endocrine & metabolic: Hyperkalemia (17% to 57%), hyperlipidemia (15%), hypokalemia (6% to 12%)
☆Gastrointestinal: Abdominal pain (8% to 38%), constipation (15% to 33%), diarrhea (6% to 20%), nausea (29% to 37%), vomiting (12% to 20%)
☆Genitourinary: Urinary tract infection (39% to 42%)
☆Hematologic & oncologic: Anemia (12% to 25%), leukocytosis (13%), leukopenia (21% to 63%), thrombocytopenia (9% to 37%)
☆Infection: Cytomegalovirus disease (6% to 13%), infection (17% to 76%; severe infection: 23%), sepsis (6% to 12%)
☆Nervous system: Anxiety (7% to 14%), chills (9% to 57%), headache (18% to 40%), insomnia (12% to 20%), malaise (9% to 13%), pain (26%)
☆Neuromuscular & skeletal: Arthralgia (15%), asthenia (13%), back pain (12%), myalgia (11% to 20%)
*OKT3
OKT3 (Orthoclone-OKT3 or Muromonab-CD3 ) is a murine monoclonal antibody specific for the CD3 antigen expressed on all human T cells.
effective as both induction therapy and in the treatment of acute rejection, but because of Of it’s serious side effects so that OKT3 is usually reserved for the treatment of severe or resistant rejection.
*Mechanism of action
• CD3 is a multimeric component of the T-cell receptor.
• Rapid (within 1 hour) activation of all CD3 cells. and cytokine release
• Clearance of >90% CD3 cells from the circulation within 24 hours
• Repeated administration is required to maintain CD3 depletion, with fully functional CD3 lymphocytes reappearing within a few days of the end of treatment
. (This is in contrast to polyclonal anti-lymphocyte Ab and alemtuzumab, both of which cause T-cell depletion persisting for months after the end of treatment).
Administration of OKT3 Precautions
Cytokine release is an unavoidable consequence of the first few doses of OKT3. Serious side effects may be minimized as follows:
• Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
• Ensure that the patient is not fluid overloaded.
Diuretics are often ineffective in the presence of AR, so use dialysis with ultrafiltration to achieve Weight within 1–2kg of dry weight
• No pulmonary oedema on CXR, and minimal peripheral oedema
• Normal BP.
• Pre-medication is essential. 30–60 minutes before the first 2 doses of OKT3 give
• IV methylprednisolone (250mg if 60kg)
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg.
• For subsequent doses, IV methylprednisolone may be replaced with maintenance oral prednisolone and the antihistamine omitted.
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
*Adverse effects
• Anaphylaxis. More common with re-exposure to OKT3.
• Cytokine release syndrome (CRS) is inevitable despite the precautions described. Almost all patients experience some symptoms 30–120 minutes after the first few doses of OKT3:
• High fever, chills and rigors in ≈90%
• ↑HR, and either ↑ or ↓ BP (30%)
• Diarrhoea and vomiting (>30%)
..Dyspnoea and bronchospasm in 10–20%, with severe non-cardiogenic pulmonary oedema in ≈2%
• Headache (30%) and aseptic meningitis. Very rarely encephalopathy, seizures and ↑ intracranial pressure (ICP) leading to brainstem herniation and death.
• ↑ infections ( especially CMV), which may be difficult to distinguish from the CRS
. • ↑ in post-transplant lymphoproliferative disorder (PTLD) by 2–3 fold in some (not all) case series.
*Polyclonal T-cell depleting antibodies
Polyclonal T-cell depleting antibodies are produced by immunizing animals with human thymic lymphocytes. The final product is purified such that it is >90% immunoglobulin, often called anti-thymocyte globulin or ATG. Several different preparations are available, and of these Thymoglobulin (rabbit ATG, or rATG) is the most frequently used. It is given as induction therapy and in treatment of acute rejection
Mechanism of action
• ATG includes antibodies against components of the T-cell receptor (CD3, CD4 and CD8), HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules.
• ATG administration has multiple effects including T-cell activation ( leading to cytokine release), clearance of T cells from the circulation, inhibition of both costimulatory and proliferative signals, and inhibition of cell adhesion and migration.
• T-cell depletion following ATG may persist for months or years (contrast with OKT3)
• ATG may have some activity to suppress B-cell and plasma cell function.
Administration of Thymoglobulin Precautions
Cytokine release leading to fever and rigors is common after the first one or two doses of any ATG preparation. Serious side effects are much less frequent than with OKT3.
• Do not give Thymoglobulin if there is untreated infection, ↓platelets or ↓WCC
• For the first dose, ensure that the patient is not fluid overloaded
.When treating AR, dialysis with ultrafiltration is required if there is pulmonary oedema.
• Pre-medication. 60 minutes before each dose of Thymoglobulin give:
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Test dose
• In some units a test dose of Thymoglobulin (5mg in 100ml 0.9% NaCl over 30 minutes into a peripheral vein) is given without pre-medication. • The aim is to exclude anaphylaxis to rabbit proteins (very unusual), which should be distinguished from the inevitable fever, chills and rigors that the test dose will precipitate.
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be 6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Adverse effects of ATG preparations
• Anaphylaxis • Cytokine release—less severe than OKT3
and largely restricted to the first dose
• ↓ WBC and platelets • ↑ infections ( especially CMV
) • ↑ in PTLD by ≈2-fold in most studies and case series
Serum sickness
• Thymoglobulin is composed of rabbit proteins, and up to 68% of patients develop antirabbit antibodies
• Very occasionally serum sickness (fever, vasculitic rash, arthralgia, and myalgia) develops as a result of immune complex formation with anti-rabbit antibodies
• Typically 5–15 days after the onset of Thymoglobulin therapy
• Self-limiting • Precludes further treatment with Thymoglobulin
• The presence of anti-rabbit antibodies alone does not preclude re-treatment with Thymoglobulin, but may reduce efficacy
. Monitoring of CD3 T cell may be required in patients receiving repeated courses.
Reference
Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011
Mujtaba Zuhair
3 years ago
OKT3 is monoclonal antibody against CD3 . it’s administration leads to depletion of T cells .
ATG is a polyclonal antibodies produced by rabbit or equine source after injection with human lymphocytes. It’s administration lead to :
T cells depletion through antibody dependent cell mediated cytotoxicity and complement-dependent cell cytotoxicity.
Less activation of T cells .
reduced leukocytes adhesion.
Also reduced numbers of B cells .
T regulatory cells are less affected by ATG , so it’s numbers are increased relative to other T cells. This can lead to graft tolerance.
Indications : OKT3 was used for treatment of steroid resistant acute cellular rejection .
some centers used it for induction of immunosuppression.
ATG : used for
treatment of acute cellular mediated rejection Banff class II and III or steroid resistant acute TCMR.
induction of immunosuppression in solid organ transplantation in high risk patients.
The use of ATG for ABMR : limited studies for the efficacy of ATG in ABMR. But there was good response for ATG in combined acute TCMR and ABMR since ATG use is associated with lower B cells.
Side effects : OKT3 : cytokine release syndrome is a major concern with OKT3 use and premedication with steroids and antihistamine should be given with monitoring of the patient . Due to this side effect and the availability of ATG , production of OKT3 had been stopped. Some patients develop antibodies against OKT3 decreasing it’s efficacy. Also fever, diarrhea , rash can occur .
ATG: Cytokine release syndrome can also occur with ATG but with lesser frequency. fever , rash , itching can occur. The most important concern with the use of ATG is the risk of infection and malignancy on the long term.
Since OKT3 production had been stopped sure I will give ATG , but even if OKT3 is available , I will give ATG because of lower toxicity and proved efficacy.
Reference:
(1) Jamal Bamoulid, Oliver Staeck , Thomas Cre´pin, Fabian Halleck
, Philippe Saas, Susanne Brakemeier , Didier Ducloux and Klemens
Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects Nephrol Dial Transplant (2017) 32: 1601–1608
doi: 10.1093/ndt/gfw368 Advance Access publication 25 October 2016
Ala Ali
Admin
3 years ago
Dear All, do you think there is a role for ATG in acute antibody-mediated rejection? Please share your thoughts
In our practice we are commencing ATG in management of ABMR beside PLEX, pulse steroids and Rituximab.
There is some retrospective studies addressed the use of ATG in the treatment of ABMR
Rabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR).rATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.
Yes ATG shows diverse effects on immune system. In addition to T cell depletion it’s also induced apoptosis in B cells lineages that interferes with dentritics cells functions and lead to expression of both T -reg cells with natural killers cells
Some clinical studies suggest that ATG reduce the AMR in patients with DSA by removing the T cells that help for B cells activation by its antibodies binding to the Many of B cells proteins and induce B cell apoptosis
ATG preferred for treatment of vascular steroid resistant ACR and ABMR
Reference
Thyroglobulin and it’s use in Renal transplantion:A review
Umasankar Mathuram Thiyagaran Amirthavarshini ponnuswamyb Atul Bagulc
And Nephrol 2013;37:586-601
• Meta-analysis that has been published 2006 studied role of monoclonal and polyclonal antibody therapy in treatment of acute rejection in kidney transplantation recipient
o Monoclonal and polyclonal antibody therapy were better than steroids in halting ongoing rejection and preventing graft loss or death with a functioning graft, but no differences in preventing subsequent rejection or death in 1 year
• KDIGO guidelines recommend corticosteroids for initial treatment of ACMR and add in maintenance prednisolone in those who are not on steroids and have rejection
Treatment of acute ABMR
• Most studies that evaluated treatment strategy of ABME had mixed rejection forms.
• One study which is retrospective analysis showed treatment of rATG based protocol (mean dose 0.79mg/kg/day) in high immunological risk had improvement in graft function and able to decrease the creatinine
• No data till now suggest rATG based induction had lesser ABMR, in fact reported 44%of those who had ATG in additional to other treatment had ABMR
• ATG is not recommended as first line treatment for ABMR
• ATG can be considered in TCMR associated ABMR
Bamoulid, J., Staeck, O., Crépin, T., Halleck, F., Saas, P., Brakemeier, S., Ducloux, D. and Budde, K., 2016. Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects. Nephrology Dialysis Transplantation, p.gfw368.
Yes, the use of ATG in the treatment of active ABMR leads to significant reduction in serum creatinine level and proteinuria and the level of peripheral lymphocytes decreased rapidly and remained so for around 12 months.
Reference: Nanmoku K., Shinzato T., Kubo T., Shimizu T., et al. Effect of Rabbit Antithymocyte Globulin on Acute and Chronic Active Antibody-Mediated Rejection After Kidney Transplantation. Transplantation Proceedings. October 2019,Vol 51,issue 8; 2602-2605.
ATG has a role in targeting the long lived plasma cells( the leading cause of ABMR) that are insensitive to the traditional B cells depleting agents.
Reference:
Su H., Zhang C.Y., Lin J., Hammes H.P. et al. The Role of Long-Lived Plasma Cells in Antibody-Mediated Rejection of Kidney Transplantation: An Update. Kidney Dis 2019;5:211–219.
ATG has a significant depleting effect on B-cells,but their effect on DSA is not ideal .
Hinda Hassan
3 years ago
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?ATG is given in cases of suspected or biopsy proven acute cellular rejection if serum creatinine does not decrease by day 4 of steroid treatment.
In your practice (in your opinion if you are not practising) what are the indications of ATG induction? Which one you prefer to give?We give ATG as induction to patients who are sensitized (high immunological risk). I prefer to give ATG because our country has much experience in its use than OKT3
Is it only given for prevention of rejection as induction therapy!? What are the other indications?
Hinda Hassan
3 years ago
Mechanism of action of OKT3 It is a murine Ig G monoclonal antibody that block CD3 .CD3 is a molecule, only in mature T cells & medullary thymocytes, near TCR which is needed for t cell activation .1 Mechanism of action of Thymoglobulin: rabbit derived polyclonal antithymocyte globulins (ATG) which results in the following (1) T-cell depletion in blood (complement dependent ) and peripheral lymphoid tissues(phagocytosis by macrophages) and depletion of activatedT-cell(through either antibody-dependent cell-mediated cytotoxicity or Fas-dependent apoptosis (2) modulation of cell surface molecules that provoke leukocyte/endothelium interactions (3) B-cell apoptosis (4) interfering with maturation and migration of dendritic cell (5) over expression of regulatory T and NK- T cells. 2 Indication of OKT3 , doses and duration of treatment: Induction and for treatment of initial and steroid-resistant rejections1 Dose is 5 mg per day in a single intravenous injection in less than one minute (not infusion) for 10 to 14 days .5
Indication of ATG, doses and duration of treatment:1- induction: 1.5 mg/kg once daily for 5–14 days or 3 mg/kg once daily on day 1 then 1.5 mg/kg once daily on days 2 and 3 2-Treatment of acute rejection : IV Infusion 1.5 mg/kg once daily for 7–14 days. 5 Mode Of Administration ATG :IV infusion through an inline 0.22-μm filter into a high-flow vein(to avoid thrombophlebitis and DVT). Allow vial to reach room T° . To the 25 mg of the drug add 5 mL of sterile water ( 5 mg/mL) and Dilute in 50 ml of 0.9% sodium chloride or 5% dextrose injection. Recommended final concentration is 0.5 mg/mL. Administer initial dose over ≥6 hours and subsequent doses over ≥4 hours. Side Effect Of OKT3:Acutely,within hours , cytokines release syndrome(fever,rigors, headache GIT side effects, dyspnoea , pulmonary edema3,Seizure,aseptic meningitis &renal insufficiency4 Side Effect Of ATG:Milder cytokines release syndrome ,thrombocytopenia,leukopenia3 Fever ,Headache ,Abdominal pain& Diarrhea 1-Norman DJ. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20. doi: 10.1097/00007691-199512000-00012. PMID: 8588230. 2- Mohty, M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia21, 1387–1394 (2007). https://doi.org/10.1038/sj.leu.2404683 3- Ernesto A. Pretto، Gianni Biancofiore، Claus Niemann، John R. Klinck، Peter D ,Oxford Textbook of Transplant Anaesthesia and Critical Care 4. Suman Kapur، Maristela Portela ,Immunosuppression: Role in Health and Diseases5-www.drugs.com
Hilda, good answer, you have answered the question ” what are the indications of ATG induction? Which one you prefer to give” in your answer with realising. Less Cytokine release with ATG and better results.
Reem Younis
3 years ago
OKT 3
-OKT3is a mouse monoclonal antibody targeted at the CD3 receptor which is a membrane protein on the surface of T cells.
-It was used to treat acute several allograft rejections but know withdrawn due to its severe side effects.
-It is given as a5mg IV bolus dose administered peripherally but doesn’t give IM.
-It is used for 10 days.
-Methylprednisolone 1mg/kg given before the first dose and IV hydrocortisone given 30 min after administration to decrease the incidence of reaction to the first dose
-A low protein-binding 0.22-micron filter is used before administration of each dose
-Patient temperature should not exceed 37.8 C at the time of administration. Side effects:
1-Anaphylaxis.
2-Cytokine release syndrome within 1st48Hr (Fever, rigors, pruritis, erythema, dyspnea, tachycardia, hypo/hypertension)
3-Very serious side effects: non-cardiogenic pulmonary edema, aseptic meningitis, and encephalopathy.
-It should not administer to volume overload patients.
-It is monitored by CD3 count. Thymoglobulin
– It is purified polyclonal immunoglobulin. Among polyclonal antibodies are antibodies specific for components of TCR (CD3, CD4, CD8) and cytokine receptors as well as adhesion molecules.
-It acts as a rapid T-cell-depleting agent in both the blood and peripheral lymphoid tissues. The major pathways for T –cell depletion are complement-dependent cell lysis in the blood compartment and apoptotic cell death in the lymphoid tissues.
-It is used as induction therapy and treatment of acute rejection inpatient receiving a kidney transplant.
– Dose is 1.5mg/kg up to 25mg in 500ml normal saline or5% glucose.
-It should be given via a central line and a 0.22-micron in-line filter is recommended.
-Administer the first dose at 10ml/h for the first hour and subsequant infusion should be administered over ≥6h.
-Treatment should not exceed 14 days.
-Premedication: chlorphenamine 10 mg IV and hydrocortisone 100mg IV 1h before each infusion. -It is monitored by CD3 count. Side effects :
1-Anaphylaxis
2-Cytokine release syndrome(Fever, rigors, pruritis, erythema, dyspnea, tachycardia, hypo/hypertension)
3-Serum sickness: after 7 days of treatment. Clinical features are fever, rash, arthralgia, myalgia. It requires treatment cessation.
4-low WCC and platelet.
5-Increase the risk of infection.
6-Increase the risk of post-transplant lymphoproliferative disorder.
7-I preferred ATG because OKT3 was withdrawn due to its severe side effects.
References
1.Sgro, C. (1995-12-20). “Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review”. Toxicology. Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology. 105 (1): 23–29
2.Simon steddon,Neil Ashman. Handbook of Nephrology and Hypertension. second addition
Muromonab CD3 (OKT3), a murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells, blocks T cell function. A rapid decrease in T-lymphocytes occurs within a few minutes after administration of muromonab CD3.It initially activates T cells, which leads to a cytokine release syndrome symptoms.
Subsequently, it both prevents T cell activation and depletes T cells.In 1986, it became the first mAb antibody approved by the FDA. It had indications for renal, cardiac, and hepatic allograft rejection. Its use was associated with a risk of infections, including bacterial, viral, and opportunistic. For this reason and the availability of alternative therapies, muromonab-CD3 was withdrawn from the market in 2010.
Antithymocyte globulin (ATG) is a polyclonal immune globulinis prepared by injecting human thymocytes into rabbits (rATG-Thymoglobulin) or horses (Atgam). Given the superior efficacy of rATG-Thymoglobulin in the treatment of acute rejection, Atgam is no longer used routinely in most transplant centers.
-Mechanism of action of Antithymocyte globulin (ATG):
ATG contains cytotoxic antibodies directed against a variety of T-cell markersinduces T lymphocyte depletion in the peripheral blood basically by complement-dependent cell lysis, inhibiting B cell proliferation and inducing B cell apoptosis. After use of Thymoglobulin, a prolonged lymphopenia can persist, and the CD4 subset may be suppressed for several years.
-Indications of Antithymocyte globulin (ATG):
1-Used as Induction therapy as T Cell depleting agent in combination with lower doses of conventional agents in patients with high risk for rejection.
Thymoglobulin (rATG) (1 to 2 mg/kg) are administered intraoperatively. The initial intraoperative dose of rATG is followed by 2 mg/kg of rATG per day for the next two days (a total of three doses of cumulative doses of 6 mg/kg) rATG is administered if the white blood cell count is greater than 2000/microL and the platelet count is greater than 75,000/microL. It is mixed in 500 mL of dextrose or saline and infused over 4 to 8 hours into a central vein.
To avoid allergic reactions, the patient should receive intravenous premedication consisting of methylprednisolone, 30 mg, and diphenhydramine hydrochloride 50 mg given 30 minutes before injection. Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control.
2-Used as anti-rejection therapy: The reversal rate for acute rejection has been between 75 and 100 percent in different series.
In biopsy proved T cell mediated rejection, Banff grade IB rejection and few or no chronic histologic lesions who present less than one-year posttransplant , in patients with Banff grade II or III rejection and in expected mixed rejection.
Commence daily rATG-Thymoglobulin at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg. The total number of doses is determined by severity of Banff grading.
CMV and PCP prophylaxis must be given during treatment with rATG-Thymoglobulin. A decrease in serum creatinine to within 10 percent of the baseline level is considered to be successful reversal of rejection.
Thymoglobulin is the preferred drug. Muromonab-CD3 (Orthoclone OKT3) is the first monoclonal antibody used in clinical medicine and was introduced in 1985. Largely because of frequent, life threatening first dose reaction, it is no longer used and in transplant is replaced by thymoglobulin. Thymoglobulin
Mechanisms of action: Thymoglobulin is a polyclonal antibody preparation. It contains cytotoxic antibodies directed against a variety of T cell markers. Its mechanism is depletion of peripheral blood lymphocyte, in particular T cells are either lysed or cleared by the reticuloendothelial system and their surface antigens may be covered by the antibody. · T cell depletion constitute the primary mechanism. · other mechanisms, such as modulation of cell surface antigens · Induces lymphocyte depletion in the peripheral blood by complement-dependent cell lysis. · Significant percentage of lymphocyte depletion can be antibody-mediated cytotoxicity and activation-induced cell death. · Depletes T cells not only in the periphery but also in secondary lymphoid tissues where the vast majority of T cells reside and antigen presentation occurs (notably not in the thymus) · Down-modulates the expression of several molecules that control T-cell activation, including the T-cell receptor (TCR)/CD3 complex, CD2, CD4, CD5, CD6, and CD8 · Down-regulate the cell surface expression of a number of integrins and intercellular adhesion molecules (ICAMs) that facilitate leukocyte adhesion to the endothelium · Strongly induce apoptosis in vitro against naive, activated B cells · Bind with numerous B-cell surface proteins and it is this cross-linking of CD30, CD38, CD95, CD80, and HLA-DR that likely accounts for this activity.
Advantages: · May reduce the risk of AMR in patients with preformed donor-specific antibody presumably by removing T-cell help for alloreactive B cells and via B-cell depletion due to antibodies which directly bind B cells · Interference with dendritic cell functional properties, and leads to induction of regulatory T and natural killer T cells. Thymoglobulin causes sustained and rapid expansion of CD4+CD25+FOXP3+regulatory T cells that play an important role in immune modulation and limiting alloimmunity. · Thymoglobulin blocks multiple antigens related to IRI, in addition to its better-known T cell depleting effects. · Treatment with thymoglobulin accompanies by lower incidence of DGF. · Lower incidence and severity of acute rejection as well as chronic rejection with treatment with thymoglobulin. · Improvement in graft and patient survival rate The complex and prolonged immunomodulation induced by ATG contributes to the efficacy of this agent. Lymphocyte depletion occurs rapidly after intravenous administration and recovery of T cell counts occurs gradually. For example, in one study, about 40% of patients treated with thymoglobulin recovered more than 50% of initial lymphocyte count in 3 months. Following administration of thymoglobulin, a prolonged lymphopenia may ensue and the CD4 population can be suppressed for several years that may account for lower frequency of rejection episodes. The standard dose of thymoglobulin is 1.5 mg/kg in a course lasting 4-10 days. Although doses above 6 mg/kg are probably not necessary for kidney transplantation. The route of administration is intravenous infusion into a central vein or arteriovenous fistula after mixing in dextrose or saline IV fluid over 4-8 hours. Administration should be started intraoperatively because there is significantly lower incidence of DGF. Premedication with methylprednisolone, diphenhydramine, and acetaminophen for prevention of allergic reaction and monitoring of vital signs are advised. Adverse effects: · Thymoglobulin can cause acute and delayed reactions. Acute reaction will present as cytokine release syndrome which is characterized by anaphylaxis, fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache which usually can be managed by stopping infusion and epinephrine. · Severe reaction includes cardiorespiratory dysfunction including hypotension, pulmonary edema, myocardial infarction, tachycardia and rarely death. · Delayed reactions usually present as serum sickness. Serum sickness tends to occur 5–15 days after the onset of thymoglobulin therapy which presents as fever, rash, arthralgia, and/or myalgia, and is treated with corticosteroids. · Thymoglobulin is not specific for T cells but contains antibodies directed against different blood cell types (T cells > B cells; NK cells > monocytes; neutrophils > platelets > erythrocytes) · Because of the presence of cross-reacting antibodies against non-lymphoid cells, hemolytic anemia, thrombosis, thrombocytopenia and neutropenia can occur. · Leukopenia and thrombocytopenia can necessitate reduction or curtailment of drug dosage. · Infection, most commonly with CMV, may be a late adverse sequela that is related to overall amount of immunosuppression. Other infections include sepsis, candidiasis, herpes simplex, and UTI. · Development of lymphoproliferative disorder (fulminant B cell lymphoma) is increased with treatment with thymoglobulin in transplant recipients. Despite these adverse effects, thymoglobulin has been shown to be safe in renal transplant recipients when administered in a planned and monitored setting. Mehrabi A, Mood ZhA, Sadeghi M, Schmied BM, Müller SA, Welsch T. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation.Nephrol Dial Transplant. 2007 Sep;22 Umasankar Mathuram Thiyagarajan, Amirthavarshini Ponnuswamy, Atul Bagul. Thymoglobulin and Its Use in Renal Transplantation: A Review. Am J Nephrol 2013;37:586–601
OKT3 is a monoclonal antibody targets CD3 antigen receptor of T-lymphocytes. while thymoglobulin is a poly antibodies against T-cell receptor (CD3 , CD4 and CD8) , HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules. thymoglobulin may have some activity against B-cell .
Administration of OKT3 can be associated with serious side effects due to rapid rebound of functional CD3 . while serious side effects are less frequent with thymoglobulin use . Efficacy
OKT3 reverses >90% of first and 66% of steroid-resistant AR episodes. The presence of anti-rabbit antibodies alone does not preclude re-treatment with Thymoglobulin, but may reduce efficacy. Monitoring of CD3 T cell may be required in patients receiving repeated courses. Adverse effects
Anaphylaxis is more common with re-exposure to OKT3.
Cytokine release syndrome (CRS) is inevitable despite the precautions . Almost all patients experience some symptoms 30–120 minutes after the first few doses of OKT3 . while in thymoglobulin cytokine release—less severe than OKT3 and largely restricted to the first dose. CRS can be seen in form of fever , headache ,vomiting ,diarrhea ,dyspnoea ,tachycardia and hypotension .
Risk of infection is increased in both.
↑ in post-transplant lymphoproliferative disorder (PTLD) is also increased in both.
Very occasionally serum sickness (fever, vasculitic rash, arthralgia, and myalgia) develops as a result of immune complex formation with anti-rabbit antibodies (thymoglobulin) . Precautions
Serious side effects may be minimized as follows:
Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
Ensure that the patient is not fluid overloaded.
No pulmonary oedema on CXR, and minimal peripheral oedema.
Normal BP. Test dose
Weight within 1–2kg of dry weight .
Pre-medication
is essential. 30–60 minutes before the first 2 doses of OKT3 and before each dose of thymoglobulin.
• IV methylprednisolone (250mg if <60kg, 500mg if >60kg) ,hydrocortisone 100 mg is enough in thymoglobulin .
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg.
•Ensure prophylaxis against PCP, CMV and oral candidiasis Dose
• OKT3 is given as an IV bolus of 5mg (2.5mg for children <30kg) into a peripheral vein. Give daily for 10 days .
In thymoglobulin;
•Induction therapy—6mg/kg, with the first dose of 1.5mg/kg administered intra operatively, and subsequent doses daily, or on postoperative days 1, 3 and 5.
•Rejection therapy—typically 1.5mg/kg daily for 10–14 days, with daily dose determined by monitoring of FBC ± CD3 cell count .
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be <0.5mg/ml).
• Thymoglobulin must be given into a central vein
• Following pre-medication, Thymoglobulin is given as an IV infusion over >6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Maintenance IS
There is a very variable approach to the administration of maintenance IS during Thymoglobulin therapy. Monitoring
•Unlike other depleting antibodies, OKT3 rarely causes thrombocytopaenia or leukopaenia.
•Efficacy can be monitored by daily flow cytometry to identify CD3 cells. If CD3 cells >0.05×10 /L then ↑ dose to 10mg daily (usually only required for repeated courses of OKT3).
Thymoglobulin monitering
Measure FBC daily
• If platelets <75×10 /L → half dose, <50×10 /L → omit
• If WCC <3.0×10 /L → half dose, <2.0×10 /L → omit.
Reference; Chang PC-W, Hricik DE. What are immunosuppressive medications? How do they work? What are their side effects? In McKay DB, Steinberg SM (eds). Kidney Transplantation: A Guide to the Care of Kidney Transplant Recipients, New York, Springer, 2010; pp 119–135. Danovitz GM. Immunosuppressive medications and protocols for kidney transplantation. In Danovitch GM (ed).
Handbook of Kidney Transplantation, 5th ed, Philadelphia, Lippincott Williams & Wilkins, 2010, pp 77–126. Kidney Transplantation- Principles and Practice. Morris PJ, Knechtle SJ (eds). Philadelphia, Elsevier Saunders, 7th ed, 2013
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Professor Ahmed Halawa
Admin
3 years ago
Dear All
In your practice (in your opinion if you are not practising) what are the indications of ATG induction?and what is the dose and the duration of treatment?
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?
high immunlogical risk patient like a-cadaveric kidney transplant b-more than 3 mismatches espically class 2 mismatches in living donation c-prevoius transplantion d-prescence of dsa befor transplantion e-abo incompatible transplantion f-postivel luuminx and negative flow cytometry crossmatch
dosage 4-6 mg kg, cumaulative dose can be given in 4 divide dose or more according to pt cbc(wbc, plt) monitoring on daily basis .
indication of atg in acute rejection?
based on histopathology and pt history of dsa befor transplantion .
banff criteria is used to deterimine the sevirty of rejection and clasissifcation of wether it is TCMR OR AMR or non immunological causes.
in AMR atg is indicated wether prescnce of c4d or not , may be accomapnied with iv igg or palsmapharesis.
IN TCMR WE USED IN OUR CENTRE TO GIVE ATG WHEN BANF GRADE 2A OR ABOVE WITH APPERANCE OF INTIMAL ARTERITIS .
Thanks prof , TYpos i will try to avoid it. Regarding my reffernce is kidgo guidlines 2009 for transplant recipent. American Journal of Transplantation 2009; 9 (Suppl 3): S6–S9
Last edited 3 years ago by MOHAMMED GAFAR medi913911@gmail.com
Indication for ATG induction therapy :
————————————————–
high immunological risk.
DD – kidney transplant.
more than 3HLA mis-match in LDT
Pediatric age group.
previous senesitization , previous kidney transplantaion , pre-transplant DSA postivewith PRA >20%
ABO incompatable transplantaion
ATG doses for induction 1.5mg/Kg given 3-4 doses , frist dose intraopertaive or post operative ( based on centre experinece ) and first 3 doses will be given daily with close monitring with FBC , lymphcytes % , total cummulative dose prefered in LD transplant not more than 6mg/ kg , RANGE 4-6mg/kg .
Indication of ATG in acute rejection
————————————————–
Steriod resistant ACR
ABMR with vascular injury as intimal arteritis sometimes diffiult to differentite by histology with the other limitation like in commertial transplantaion we cant perform DSA , so in suspected cases of vascular involvemnt with intimal artirtits will go ahead with ATG to cover for possible mixed type of rejections.
dosing same 1.5mg /kg for 3-4 doses depend on response and toleration of the therapy, total cummulative doses of ATG for induction and rejection treatment should not be more than 9mg/kg in order to aviod serious side effects including the apportunesitic infections like CMV, PJP and malignancies .
prefered to give CMV prophylaxis in the first 6 weeks of the course with transient reduction of MMF dosing .
Adding to the list of high risk and prefere induction with ATG :
————————————————————————————
younger recipient and old donor.
DGF .
Long cold ischemia time> than 24h .
black race
some centres including ours we use ATG even in LD with low immunologic risk with dose modifications less frequency and lower cummulative doses 1-1.5mg/kg of 3-4 doses maximum ,as we have only ATG as induction IS we have limited access to monoclonal AB like basiliximab or donzamab.
-UpTODATE,, kidney transplantation in adult: induction immunosuppressive therapy , 2021.
indications of ATG induction:
1- high immunological risk patient like DSA pretransplant , PLNF(positive luminex negative flow cytometry), 2nd or more transplant.
2- deceased donor
3- female recipient with male donor.
4- African recipient.
dose 1.5 mg/kg/dose for 3-7 days , given over 4- 6 hrs iv infusion in central line , with premidication used as paracetamol injection, methylprednisolone and antihistaminic iv,
3 mg /kg is the 1st dose given intraoperative. ATG in acute rejection :
used to treat acute cellular rejection not responding to pulse steroid therapy (resistant) which may be alone or mixed with antibody mediated rejection (which is treated originally by plasmapharesis and IVIg)
Induction immunosuppressive therapy in kidney transplantation depends on the recipient’s risk of acute rejection. In patients with high risk for rejection, r-ATG is given instead of anti IL2.
According to 2009 KDIGO clinical practice guidelines, risk factors for acute rejection include one or more of the following:
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African-American ethnicity (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Route of administration
The first dose is given over at least 6 hours; subsequent doses may be infused over at least 4 hours. Infuse through a central line but can also be given in peripheral line. To avoid or to reduce severity of infusion related reactions, premedicate with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to infusion.
Dose
For induction therapy r-ATG is given IV at 1.5 mg/kg/day for 4 to 7 days with the first dose should be started in the way to the surgery.
For acute rejection r-ATG is given at dose of 1.5 mg/kg/day IV for 7-14 days
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African-American ethnicity
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
In such patients, the 2009 KDIGO guidelines suggest the use of lymphocyte-depleting agents, which are potent immunosuppressive agents, rather than interleukin (IL) 2 receptor antibodies.
*ATG therapy indicated in (TCR) in the following
if there is any evidence of vascular involvement (Banff 2A)
Banff 2B/3 rejection
Steroid-resistant
*ATG therapy indicated in (AMR) in the following
AMR is almost always associated with TCMR, and in any case Ab-mediated immune responses require T cell help.
Treat vascular inflammation and TCMR with :
• IV methylprednisolone for the first 3 days of treatment
• T-cell-depleting Ab (Administer after PEX/IA treatment, or on non-PEX/IA days.)
*Dosing strategies for rATG-Thymoglobulin
Our practice
●seven-day course of rATG-Thymoglobulin at 1.5 mg/kg intravenously 6–8 hours via central line intraoperatively, then daily for six days.
Reference
1-Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011
In your practice (in your opinion if you are not practising) what are the indications of ATG induction?and what is the dose and the duration of treatment?
ATG is used for induction in high immunological risk transplantation as:
highly sensitized patients
cadaveric renal transplantation
ABO incompatible transplantation
The dose for induction is 1-1.5 mg/kg, the duration is from 4-14 days.
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?
In cell mediated rejection the indication is steroid unresponsive acute TCM rejection. In ABMR the indication is in case of unresponsiveness to other immunosuppressive medications as this type of ABMR is thought to be caused by long lived plasma cells that are insensitive to traditional immunosuppressive that remove B cells.
Reference: Su H., Zhang C.Y., Lin J., Hammes H.P., et al.The Role of Long-Lived Plasma Cells in Antibody-Mediated Rejection of Kidney Transplantation: An Update.Kidney Dis 2019;5:211–219.
Indication for the treatment and prevention of acute transplant rejection.
for the treatment of T cells acute lymphoblastic leukemia
Side effects
-flu-like “cytokine-release syndrome” symptoms, headaches, diarrhea, nausea, and vomiting.
-may lead to life threatening status ; apnea, flash pulmonary edema and cardiac arrest.
-Leucopenia and neurological side effects
-Increases risk of infections, including bacterial, viral, and opportunistic.
Mode of administration
IV administration with 100% bioavailability
Mechanism of action
-induces lymphocyte depletion by complement-dependent cell lysis which is not the only mechanism as a large percentage of lymphocyte depletion can be done by antibody-mediated cytotoxicity
-in lower conecntations it induce lysis of preactivated T cells while at higher concentration it triggers CD178 (CD95-L) expression by resting T cells and apoptosis of preactivated T cells by mostly involving Fas/Fas-L interactions
-can cause apoptosis to activated B cells and bone marrow resident plasma cells it binds with numerous B-cell surface proteins and it is the cross-linking of CD30, CD38, CD95, CD80, and HLA-DR that likely enables this activity.
-Also it interference with dendritic cell functional properties, and leads to induction of regulatory T and natural killer T cells.(#)
Indication – for the prophylaxis and treatment of acute rejection in transplanted patients with concomitant immunosuppression – Aplastic anemia -Myelodysplasia -Graft versus host disease
Mode of administration
IV route recommended before admistration to give corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion; to reduce the infusion-associated reactions
Infuse first dose over at least 6 hr and the following doses over at least 4 hr
Stored refrigerated between 2-8°C , need to be protected from light and freezing
References
Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.
(#)Thiyagarajan UM etal. Thymoglobulin and Its Use in Renal Transplantation: A Review. Am J Nephrol 2013;37:586–601
Thanks Doaa OKT3 is withdrawn from the market and not in use any more due to its side effect
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
1-WHAT IS THYMOGLOBULIN?
polyclonal antibodies made by immunization of rabbits with human lymphoid tissue . and then harvesting the resultant immune sera to obtain gammaglobulin fractions.
a- mechanism of action,
the product contain cytotoxic antibodies directed against a variety of T-cell markers. After their administration, there is depletion of peripheral blood lymphocytes. The lymphocytes, T cells in particular, are either lysed or cleared by the reticuloendothelial system, and their surface antigens may be masked by the antibody. Of particular importance.
b- dosage form
for induction immuonsuprrion and rejection eposiode like AMR 4-6 mg kg/cumulative dose didved on 4-10 days given in central line over 4-8 hours , (can be given in av fistula mixed with 1000 unit of heparin to prenent thrombosis), porceded by 1000 mg of actiamenophenand diphynhydramine to prevent allerigic reactions
c-side effects
during adminstration, fever ,chills and may cause svere anaphylactic recations and adminstrian sulod be stopped at this level, serum sickness rarely occurs becausse of pre adminstion drugs given .
after adminstrioan , lecuopeina mayoccur up to 50% and also trhromboytopenia , and next dose should be halved either a platelet count of 50,000 to 75,000 cells/mL or a white blood cell count of less than 3,000 cells/mL and if the wbc or platelt still contiue to drop on daily basis assement ,atg should be hold till recovery of both values.
also Infection, most commonly with CMV, may be a late adverse sequela of depleting antibody use.
2-WHAT IS OKT3 ?
a-MECHISM OF ACTION Orthoclone OKT3 (muromonab-CD3) was the first monoclonal antibody used in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface. OKT3 reacts with and blocks the function of a 20,000-dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following Orthoclone OKT3 administration
b-dosage form dose 5mg to be geive through intravenous infusion (Iv) through mill pore filter as bolus dose with premedications . Daily dose for 10 days, some they give shorter course 5 days, preferred to be given in hospital due to risk of sever life threatening side effect following first few doses due to cytokines release syndrome as the patient will have fever rigor with in first hour of the infusion and remain for 2-3 days after induction with OKT3.
i dont have any expeirnce in dealing with okt3 so i used to give rTAG for high immulogical risk pt.
reffrences
1-Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
2-handbook of kidney transplantion third edition
saja Mohammed
3 years ago
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action, indication, side effect and mode of administration? Which one you prefer to give?
Whats the difference between monoclonal and polyclonal ABS:
Monoclonal antibodies (m ABs) they are homogenous AB , every AB is identical in its protein sequence so expected every antibody to have the same antigen recognition site ,affinity biologic interaction and downstream biologic effects , while the polyclonal ABs are heterogenous in protein sequence and recognize heterogenous epitopes on an antigens.
OKT3 muromonab – AB (m-ABS, IgG) :
this drug has been inuse since 1987 for both induction and treatment of acute rejection by inducingT-cell depletion effect by binding to the subunit of the CD3 complex receptors lead to subsequent deactivation and endocytosis ofCD3 complex and also deactivate the killer Tcells.
Dose and administration, side effects:
OKT3 standard dose 5mg to be geive through intravenous infusion (Iv) through mill pore filter as bolus dose with premedications .
Daily dose for 10 days, some they give shorter course 5 days, preferred to be given in hospital due to risk of sever life threatening side effect following first few doses due to cytokines release syndrome as the patient will have fever rigor with in first hour of the infusion and remain for 2-3 days after induction with OKT3 , if fever prolonged for more than 3 days should consider investigation for infection
Infection risk is high with both monoclonal and polyclonal depleting agents
Non cardiogenic pulmonary edema is one of life-threatening side effect after the first or second dose of OKT 3 especially in patient with volume overload thats why it’s important to ensure good UF prior to OKT3 administration and need close monitoring of volume status during the induction therapy.
Neurological side effects vary from mild headache to encephalopathy and aseptic meningitis.
Malignancy, increased risk of lymphoma .
Rejection rate up to 60% but usually mild with good response to steroid pulses with good maintenance IS with CNI based.
Because of wide spectrum of side effect and cost in addition with the introduction of the new different types of mABs since 1990s in the markets this drug no more consider as part of induction protocol world wide and in US its removed from the protocols ,Im not familiar with its use its not part of our transplant protocaol.
Polyclonal thymoglobulin Abs:
Rabbit ATG, thymoglobulin,prepared by immunization of rabbits with human lymphoid tissue. Atgam which is made from immunizations of horses with human lymphoid tissues.
Thymoglobulin ( Gnezyme ) in USA
ATG Fresenius in Europe (Activated human T cells).The exact mechanism of action not fully understood, its act as peripheral blood lymphocytes depleting agent, it causes sustained and rapid expansion of the CD4, CD25, Foxp3 Treg that play central part in sustained suppression of immune response and reduce the risk of rejection
CD4 can be suppressed for years following the ATG therapy. Indication, administration:
ATG polyclonal AB used for both induction protocols and treatment of rejections, both steroid resistant ACR and ABMR , mixed type rejections .
ATG always should be given in hospital setting prefered through central line for slow IV infusion 6-8 hours with premedication’s like IV paracetamol antihistamine and IV steroid to avoid anaphylaxis allergic reaction some they preferred to be given in ICU setting.
Standard dose for induction 1-1.5mg /Kg,first dose tobe given intra- operative and then daily with close FU with FBC,WBC and the lymphocytes percentage ,vitals to be checked every 15 minutes in first hour and then hourly total dose should not exceed 6mg/kg ,and total accumulative dose for any rejection episodes should not more than 9mg/kg due to the side effect on long term including malignancy and opportunistic infections
During use of ATG preferred to hold other IS medication like MMF and reduce the dose of CNI to avoid further worsening of hematological side effects including bone marrow suppression and increased infection rate
Side effects of polyclonal ATG
1-Allergic reaction including anaphylaxis, fever rigor arthralgia and rare event of serum sickness when patient will develop fever, arthralgia, malaise, rash usually responding to steroids, allergic side effect is less compared to OKT3 mABs.
2-Hematological side effect like leucopenia thrombocytopenia ,we need close monitor and dose reduction and spacing if wbc count < 3000 ,platelet count 50-100,000 ,and even stop if WBC < 2000 and ;lymphocytes % < 0.1% .
3-Infectionincluding CMVit depends on total courses and total cumulative dose of ATG its can be late side effect that’s why some centers they start CMV prophylaxis therapy either before or during the ATG depleting course especially in recipient with +ve CMV serology.
4- Malignancy, one of the concerning side effects of ATG is the lymphoma post-transplant especially recipient with EBV negative serology and donor + including aggressive type B -cell lymphoma which is fatal and aggresive that can developed with in the first months post transplantation.
Which one you prefer to give?
I’m currnetly very familiar with ATG polyclonal AB( thymoglobulin , Gnezyme ),its part of our transplant protocol for induction using it as intra-operative infusion for first dose followed by another 2-3 doses its depends ,total doses not more than 4.5-6mg /kg for induction protocol,also we used for treatment of steroid resistant ACR,and mixed rejection ABMR/ACR .using through centrral and peripheral in e that well secures as slow iv infusion over 6-8 hours by peripheral line and 4-6 hours through central linewith premedication 30 minutes prior to the infusion ( IV paracetomal 1gm and PMP250mg ,antihiatmine 10mg iv ), we monitor with FBC and% of lymphocytes.
References: Handbook of kidney transplantation by Gabriel M. Danovitch, FifithEdition.
Orthoclone muromonab-CD3: mechanism of action:
Lymphocyte depleting antibodies that target the CD3 complex on T cells leading to inhibition of activation and proliferation of T cells. (1) indications:
discontinued from clinical use
was used in induction therapy (1)
was approved for treatment of acute steroid resistant rejection of solid organ transplant. (2) Side effects:
first dose reaction due to cytokine release and may lead to capillary leak syndrome with pulmonary edema and respiratory failure (3)
treatment failure due to development of anti-OKT3 antibodies (4)
studies showed increased risk of post transplant lymphoproliferative disease with OKT3 (5) Mode of administration:
5mg IV bolus daily for 10 days
Thymoglobulin: mechanism of action:
Polyclonal immunoglobulin G directed against multiple T cell antigens
lymphocyte depletion through: (6)
antibody dependent cell cytotoxicity
complement dependent cell cytotoxicity where antibodies fix complement C1q and form membrane attack complex causing lysis of T cells
opsonization process and phagocytosis of antibody recovered T lymphocytes by reticuloendothelial system
T lymphocytes apoptosis through upregulation of CD178 expression
decrease activation of T cells through downregulation of TCR/CD3 complex. (7) Indication:
Prophylactic induction therapy to reduce the rate of early graft rejection and allow early withdrawal of steroids. (8) decrease incidence of delayed graft function especially when started intraoperatively. (9)
KDIGO guidelines recommend using T cell depleting antibodies for induction in patients with high immunological risk (10)
KDIGO guidelines suggest using T cell depleting antibodies in treatment of recurrent acute cellular rejection that don’t respond to corticosteroids (10) Side effects:
Cytokine release with rapid infusion
thrombocytopenia and leucopenia in 50% of patients. (9)
increase risk of postoperative opportunistic infections (CMV is the most common) (9) increase risk of malignancy especially post transplant lymphoproliferative disease. (11) Mode of administration (9)
standard dose of rATG is 1.5 mg/Kg for 4-10 days.
administered in central vein
to avoid allergic reaction, acetaminophen, diphenhydramine hydrochloride and hydrocortisone given as premedication
vital signs are monitored during administration
The dose should be halved if platelets count 50,000-75,000 or white blood cell count <3,000 and should be stopped if count decrease more.
Therapeutic effect monitored by absolute count of lymphocytes <0.1%
(1) Norman DJ, Kahana L, Stuart FP, et al: A randomized clinical trial of induction therapy with OKT3 in kidney transplantation. Transplantation 55:44-50, 1993.
(2)Grgic, I. and Chandraker, A., 2018. Significance of biologics in renal transplantation: past, present, and future. Current opinion in organ transplantation, 23(1), pp.51-62.
(3) Padiyar, A., Augustine, J.J. and Hricik, D.E., 2009. Induction antibody therapy in kidney transplantation. American journal of kidney diseases, 54(5), pp.935-944.
(4) Chouhan KK, Zhang R. Antibody induction therapy in adult kidney transplantation: a controversy continues. World J Transplant 2012; 2:19–26
(5) Opelz G, Dohler B: Lymphomas after solid organ transplantation: A Collaborative Transplant Study report. Am J Transplant 4:222-230, 2003
(6) Mueller TF. Mechanisms of action of thymoglobulin. Transplantation 2007;
84: 5–10
(7) . Pre´ville X, Flacher M, LeMauff B et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 2001; 71: 460–468
(8) Malvezzi P, Jouve T, Rostaing L. Induction by anti-thymocyte globulins in
kidney transplantation: a review of the literature and current usage. J Nephropathol 2015; 4: 110–115
(9) Handbook of kidney transplantation by Gabriel M. Danovitch, Sixth Edition
(10) Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9: S1–S157
(11) Lim WH, Turner RM, Chapman JR et al. Acute rejection, T-cell-depleting antibodies, and cancer after transplantation. Transplantation 2014; 97:817–825
Thank you Heba for your answer .Just emphasizing some points:
the ceiling level for repeated cources of ATG is limited by a total cumulative dose in repeated rejection is not more than 9mg/kgm.
during ATG cource reduce or dc. the antimetamolites MMF.
Weam Elnazer
3 years ago
Thymoglobulin: Dosage and Administration
Induction: 1.5 mg /kg/dose (actualbody weight) (roundto the nearest 25 mg) Before each dose, the patient may be pretreated with diphenhydramine 25- 50 mg POIIV and acetaminophen 650 mg PO 1 hr prior infusion.
Thymoglobulin should be given after the scheduled methylprednisolone dose Thymoglobulin dose must be diluted in normal saline (usually 250 mL] to a
concentrationnotexceeding0.5 mg/mL.
1st dose should be infused over a minimum of 6 hrs into a central line through
an in-line 0.22 pm filter. Subsequent doses can be given over 4 hrs.
Peripheral administration: Thymoglobulin should always be given through a central line, however, peripheral administration has been used in Europe (not approved in the USA). For peripheral administration thymoglobulin should be diluted in 500 cc NS, heparin 1000 units and hydrocortisone (20-100 mg) are added to the bag.
Monitoring
Vital signs (temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation] should be monitored prior to the start of the infusion, then every 15 minutes for the first hour, then every 30 minutes for the second hour, and then hourly until the end of the infusion.
OKT3 – OKT3 (Muronab-CD3, Orthoclone)
was the first monoclonal anti lymphocyte antibody used in clinical transplantation.
It binds to the lymphocyte CD3 complex, resulting in rapid cell lysis, therefore inhibiting almost all T-cell functions.
Currently, few pediatric transplant recipients receive OKT3 for induction therapy because there is no clear benefit of OKT3 compared with other anti lymphocyte antibody preparations and it has significant adverse effects.
This includes the “first-dose reaction,” which occurs in more than two-thirds of patients, and consists of fever, chills, headache, vomiting, diarrhoea, hypotension, and occasionally pulmonary oedema. In addition, the use of OKT3 is limited by the formation of anti-OKT3 antibodies, which commonly occurs in children.
I think because of side effects and no significant benefit above ATG.OKT3 of limited use
uptodate.com
fakhriya Alalawi
3 years ago
Antilymphocyte antibodies – Antilymphocyte antibodies include both polyclonal and monoclonal antibodies. Thymoglobulin is a polyclonal immunosuppressive agent that is generated in rabbits, commonly referred to as rabbit antithymocyte globulin, or rATG. Thymoglobulin is indicated as induction therapy and as a treatment of acute rejection in patients receiving a kidney transplant. Polyclonal antibodies contain antibodies to a wide variety of human T-cell surface antigens, including the major histocompatibility complex (MHC) antigens. Another polyclonal antibody, Atgam, is a purified gamma globulin solution. It is obtained by immunization of horses with human thymocytes. Thymoglobulins is given as slow infusion. Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to each infusion of Thymoglobulin is recommended and may reduce the incidence and intensity of infusion-associated reactions.
Serious immune-mediated reactions, including anaphylaxis or severe cytokine release syndrome (CRS), have been reported with the use of Thymoglobulin. Fatal anaphylaxis has been reported. Other adverse effects include hematologic effects, such as low counts of platelets and white blood cells (including low counts of lymphocytes and neutrophils), Infection, Malignancy, urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, and increased potassium levels in the blood. Orthoclone OKT3 (muromonab-CD3) was the first monoclonal antibody used in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface.OKT3 reacts with and blocks the function of a 20,000-dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following Orthoclone OKT3 administration.
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. Also OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. Anaphylactic and anaphylactoid reactions may occur following administration of any dose or course of Orthoclone OKT3. In addition, serious, occasionally life-threatening, systemic, cardiovascular, and central nervous system reactions have been reported following administration of Orthoclone OKT3. These have included: pulmonary oedema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral oedema, cerebral herniation, blindness, and paralysis. Pre-treatment with methylprednisolone is recommended to minimize symptoms of Cytokine Release Syndrome. References: 1. Norman DJ, Leone MR. The role of OKT3 in clinical transplantation. Pediatric nephrology. 1991 Jan;5(1):130-6. 2. Manis JP, Feldweg AM. Overview of therapeutic monoclonal antibodies. UpToDate. Waltham, MA: UpToDate Inc.[ažurirano 08.05. 2020. Accessed on Nov 2021 3. https://www.drugs.com/pro/orthoclone-okt3.html, accessed on Nov 2021 4. https://www.drugs.com/pro/thymoglobulin.html , accessed on Nov 2021
Thymoglobulin the mechanism is not fully understood but depletion of lymphocytes does occur .OKT3 blocks T cell function by direct monoclonal antibody against CD3 .Both are indicated in treatment of acute rejection .ATG also use as induction .side effect both of them cause fever, nausea ,SOB and chills . ATG cause hyperkalemia ,leucopenia and high blood pressure .OKT3 cause abnormal heart rhythm ,chest pain and dizziness . ATG 1.5mg/kg in NaCl over 6-8 hour via central line .OKT3 2hour infusion to reduce side effects .
Thanks Dalia
This is a very short answer. Please expand.
Sherif Yusuf
3 years ago
Antilymphocyte antibodies are antibodies that kill bound T lymphocytes, 2 types exists :
A- Polyclonal antibodies : antibodies produced to many hematopoietic antigens (CD2, 3, 4 ,8, 18) raised from animals (rabbit, hoarse), immunized with human lymphocytes, lymphoblast or thymocytes, 2 preparations are available :
1. Anti-thymocyte globulin (ATGAM) derived from horse
2. rATG-thymoglobulin derived from rabbit
NB: Incidence of acute rejection was found to be lower in patients receiving rATG- thymoglobulin when compared to ATGAM.
B- Monoclonal antibodies : are antibodies produced to specific TCR, include the following
1. OKT3 – OKT3 (Muronab-CD3, Orthoclone)
2. Alemtuzumab (Campath-1H) – humanized panlymphocytic (both B and T cells) anti-CD52 antibody .
rATG (thymoglobulin)
Mechanism of action :
A polyclonal antibodies to many hematopoietic antigens, raised from rabbet, immunized with human lymphocytes.
Indications :
1. Induction treatment for high risk renal transplant patients
2. Treatment of cell medicated rejection or combined cell and ABMR, Banff grade IB (if patient present in first year post transplant and biopsy revealed low chronicity index) or Banff grade II or III.
Side effects :
1. Infusion reactions (fever, chills, headache, diarrhea, hypotension, vomiting, may be ARDS)
2. Pancytopenia
3. Increase risk of infections especially CMV
4. Increase risk of EBV related PTLD
Mode of administration and dosage :
A- For Induction therapy
⦁ rATG is given intravenously in a dose of 1-2 mg/kg/d (starting intraoperatively before reperfusion of donor kidney) in combination with methylprednisolone in a dose of 7 mg/kg intraoperatively
⦁ if contraindicated basiliximab can be given
B- For acute rejection treatment
⦁ IV: 1.5 mg/kg/day for 4-6 days in combination with methylprednisolone at 3-5 mg/kg /d for 3-5
⦁ if contraindicated alemtuzumab can be given
General rules:
⦁ The optimal cumulative dose is not set till now but dose < 3 mg /kg and > 6 mg/kg are not recommended, use lower cutoff for low risk patients and higher cuttoff for high risk patients
⦁ Daily CBC is done if WBCS < 2000 microL or platelets < 75000microL the next dose is skipped, and If WBCS between 2000-3000 microL or platelets between 75000-100000 microL the next dose is halved.
⦁ No dosage adjustment required for renal or hepatic impairment
⦁ The drug is supplied in the form of 10 ml vial containing 25 mg rATG
⦁ First dose should be infused over at least 6 hrs , subsequent doses may be infused over at least 4 hours.
⦁ Should be infused through a high-flow vein (central line)
⦁ Premedication with corticosteroids, acetaminophen and antihistamine is recommended 1 hour prior to infusion
⦁ If severe reaction occur stop and if mild reaction occur decrease the rate of infusion
OKT-3
Mechanism of action :
⦁ OKT-3 is a monoclonal AB which binds to lymphocyte CD3 complex leading to rapid lysis.
⦁ It is the first monoclonal AB used in transplantation
Indications :
Approved only in the treatment of acute allograft rejection not for induction, although it is used for induction by few centers in pediatric clinical transplantation.
Side effects :
⦁ First dose infusion reaction (cytokine release syndrome) including (fever, chills, headache, diarrhea, hypotension, vomiting, and may cause severe pulmonary edema) infusion reaction occur in > 2 third of the patients after 30-60 mins of infusion
⦁ Anaphylactic reactions same manifestation of cytokine release syndrome but usually occur earlies after 10 min.
⦁ Formation of anti-OKT3 antibodies leading to resistance to treatment which is more common in children
⦁ CNS side effects including headache, seizures, aseptic meningitis, encephalopathy, cerebral edema, fatal cerebral herniations due to cerebral edema
⦁ Increase risk of infections especially CMV
⦁ Increase risk of EBV related PTLD
Mode of administration and dosage :
⦁ OKT-3 is a monoclonal AB which binds to lymphocyte CD3 complex leading to rapid lysis.
⦁ It is the first monoclonal AB used in transplantation
⦁ Premedication with corticosteroids, acetaminophen and antihistamine is recommended 1 hour prior to IV shot.
I prefer to use rATG because of the following :
1- The effect of rATG is comparable to OKT3
2- Side effects of OKT3 are more serious than those experienced by r ATG especially cytokine release syndrome (pulmonary edema) and CNS side effects (cerebral edema)
3- OKT3 is given by bolus injection so no action could be done as decreasing or stopping infusion like rATG.
REFERANCES
1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-203
2. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
3. Kutzler HL, Ye X, Rochon C, Martin ST. Administration of antithymocyte globulin (rabbit) to treat a severe, mixed rejection episode in a pregnant renal transplant recipient. Pharmacotherapy. 2016;36(4):e18‐e22.
4. Adair JC, Woodley SL, O’Connell JB, et al. Aseptic Meningitis following Cardiac Transplantation: Clinical Characteristics and Relationship to Immunosuppressive Regimen. NeuChatenoud L, Legendre C, Ferran C, et al. Corticosteroid Inhibition of the OKT3 – Induced Cytokine-Related Syndrome – Dosage and Kinetics Prerequisites. Transplantation 51:334–338, 1991.
5. Cockfield SM, Preiksaitis J, Harvey E, Jones C, Herbert D, Keown P, and Halloran PF, et al. Is Sequential Use of ALG and OKT3 in Renal Transplants Associated with an Increased Incidence of Fulminant Post Transplant Lymphoproliferative Disorders? Transplant. Proc. 23:1106–1107, 1991.rology 41:249–252, 1991.
ATG is a polyclonal IgG obtained from sera of horses & rabbits which immunized with human lymphocytes. After administered by IV infusion it will induce rapid T-cells depletion through different mechanisms:
Ab-mediated cell cytotoxicity
complement dependent cell cytotoxicity.
opsonization
activation-induced cell death.
Also ATG can control B cells activation & Ab formation through:
interference with T cells dependent activation of reactive B cells by removing CD4 T cells.
binding of surfaces proteins which present in both T &B cells with subsequent complement mediated B cell lysis.
binding to specific B cell surface markers that interfere with B cells activation & induce apoptosis.
ATG used as induction therapy for sensitized pre transplant patients & as treatment of acute cellular rejection, steroid resistant rejection & acute ABMR. Its side effects include low grade fever, arthralgia & cills but severe reaction is rare.
OKT3: it is a murine monoclonal Ab of IgG2A against CD3 part of Cell receptor, it block T cell function but has limited effect on other tissues & cells.
It given by IV route & need premedication with steroid, acetaminophen & diphenhydramine to prevent the side effects like cytokine release syndrome & pulmonary edema, so it should be avoided in hypervoleumic patients although it can occur in euvoleumic patients.
It used for prevention & treatment of acute rejection ( especially steroid resistant rejection).
References :
Bamoulis S., Steack O., Crepin T., et al. Anti-thymocyte globulins in kidneytransplntation: focus on current indications and long-term immunological side effects. Nephrol Dial Transplant, 2017; 32: 1601-1608.
Handbook of Transplantation. Danovitch G. 6th edition
medscape
Assafi Mohammed
3 years ago
OKT3
A murine monoclonal antibody. mechanism of action of Muromonab CD3 (OKT3): a murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells, blocks T cell function. A rapid decrease in T-lymphocytes occurs within a few minutes after administration of muromonab CD3.
indication:
1.This antibody is used mainly in renal, liver and heart transplant:
treatment of acute organ rejection
induction before transplant (lymphocyte depleting agent.
2.It is also used in T cells acute lymphoblastic leukemia.
Dosage:
It is administered in a dose of 5 mg through IV push every day for 10–14 days (Hooks et al., 1991)
side effec
The first doses of muromonab CD3 are associated with a flu-like “cytokine-release syndrome” symptoms, including fever, chills, and gastrointestinal disturbances.
Other common adverse reactions associated with its use include headaches, diarrhea, nausea, and vomiting.
May lead to life threatening situation i.e; apnea, flash pulmonary edema and cardiac arrest.
Leucopenia and neurological side effects (encephalopathy and aseptic meningitis) have also been observed.
Tachyphylaxis has been reported in case of repeated administration.
Predisposition to PTLD.
contraindication
The drug is contraindicated in condition like heart failure, epilepsy, allergy pregnancy and uncontrolled arterial hypertension
THYMOGLOBULIN Thymoglobulin® (anti-thymocyte globulin [rabbit]) is a purified, pasteurized, immunoglobulin G, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. mechanism of action
Thymoglobulin acts as a rapid T-cell depleting agent, primarily through complement-dependent cell lysis in the blood compartment and apoptotic cell death in lymphoid tissues.
Although the primary immunosuppressive effect is T-cell depletion, Thymoglobulin has also been shown to modulate cell surface markers, including a number of integrins and intercellular adhesion molecules that facilitate leukocyte adhesion to the endothelium.
Thymoglobulin is not specific for T cells but contains antibodies directed against different blood cell types (T cells > B cells; NK cells > monocytes; neutrophils > platelets > erythrocytes).
Dosage
About 40% patients treated with thymoglobulin (mean of 6 doses at 1.5 mg/kg/day) recover more than 50% of initial lymphocyte count at 3 months [Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, Dolan S, Kano JM, Mahon M, Schnitzler MA, Woodward R, Irish W, Singer GG: A randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation 1999;67:1011-1018.].
indication
Prevention and Treatment of rejection following renal transplantation.
A Review Article by Thiyagarajan et al consolidates up-to-date available evidence to address the therapeutic role of thymoglobulin in (i) immunological tolerance, (ii) ischemia perfusion, (iii) live donor transplantation, (iv) delayed graft function,(v) prevention and treatment of rejection, (vi) graft survival and (vii) post-transplant lymphoproliferative disorder following renal transplantation.
{Thymoglobulin and Its Use in Renal Transplantation: A Review , Thiyagarajan U.M.a · Ponnuswamy A.b · Bagul A.c ; Am J Nephrol 2013;37:586-601 https://doi.org/10.1159/000351643}
Side Effects 1.Acute and early reaction: will present as cytokine release syndrome which is characterised by anaphylaxis, fever, chills/rigors, dyspnoea, nausea/vomiting, diarrhoea, hypotension or hypertension, malaise, rash, and/or headache which usually can be managed by stopping infusion and epinephrine. 2.Severe reaction includes cardiorespiratory dysfunction including hypotension, pulmonary oedema, myocardial infarction, tachycardia and rarely death. 3.Delayed reactions usually present as (i) serum sickness and (ii) infections.
Serum sickness tends to occur 5-15 days after onset of thymoglobulin therapy which presents as fever, rash, arthralgia, and/or myalgia, and are treated with corticosteroids. Despite these adverse effects, thymoglobulin has been shown to be safe in renal transplant recipients when administered in a planned and monitored setting.
Infectious complications include cytomegalovirus (CMV) infection (13.4%), sepsis (12.2%), candidiasis (3.7%), herpes simplex (4.9%) and urinary infections (18.3%). These infectious episodes were present when the total dose of thymoglobulin was >7 mg/kg.{Clesca P, Dirlando M, Park SI, García R, Ferraz E, Pinheiro-Machado PG, Kushnaroff L, Tedesco-Silva H Jr, Medina-Pestana JO: Thymoglobulin and rate of infectious complications after transplantation. Transplant Proc 2007;39:463-464}
Last edited 3 years ago by Assafi Mohammed
Riham Marzouk
3 years ago
OKT3
It is muromonab-CD3 murine monoclonal antibody of immunoglobulin 2A clones to the CD3 portion of the T-cell receptor. It is the first monoclonal antibody.
Mechanism of action: it is antibody directed against CD3 which molecule part from multicomplex molecule on the surface of mature T cell close to TCR ( T cell receptor), there is association between CD3 and TCR , so the block of CD3 will affect T cell activation. It blocks function and generation of T cells.
After initial dose of OKT3 , T lymphocytes that express CD3 disappeared soon , it cause opsonization/internalization of CD3. CD3 will reappear back after 48 hrs of discontinuation of OKT3.
Side effects: Cytokine release syndrome
( fever, hypotension, dyspnea, headache), pulmonary edema in hypervolemic or even euvolemic patients may occur.
It is immunogenic; antibodies can be formed against it so subsequent doses will be ineffective in most of cases.
PTLD (post-transplant lymphoproliferative disease).
indications: Induction immunosuppression.
Treatment of primary acute rejection.
Treatment of steroid resistant rejection.
Used in ATG resistant rejection.
Can be monitored by CD3 antigen assay.
Mode of administration: Premedication should be given to guard against cytokine release syndrome like steroid, acetaminophen, and diphenhydramine. Given by 2hrs iv infusion.
References: D J Norman. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20.
It is polyclonal rabbit antithymocyte globulin, it is a mixture of different antibodies specificities.
Also there is horse ATG (hATG).
Mechanism of action:
It interact with different antigens involved in immune response, and adhesion molecules.
It is T cell depleting agent , cause complement dependent cell lysis in the blood and apoptosis of T cells in lymphoid tissues.
It modulate cell surface markers and adhesion molecules so prevent leucocytes adhesion to endothelium.
This depletion of effector T cells will increase in Treg numbers , so facilitate immunosuppression or inhibitory action of immune system.
side effects:
Cytokine release syndrome
Pancytopenia.
PTLD
indications:
Induction immunosuppression.
Treatment of allograft rejection and graft versus host disease GVHD.
Treatment of aplastic anemia.
Mode of administration:
Given by IV infusion over 4-6 hrs with premedication to guard aginst cytokine release syndrome.
OKT3 ( muromonab) is a murine monoclonal antibody of IgG2 isotype, it acts by targeting CD3, block both the generation and function of effector T cells. it react with peripheral peripheral blood T cells, body tissue T cells but not other hematopoietic elements.
it is used for induction and treatment of acute allograft rejection,it’s action lasts for 7 days. side effects include cytokine release syndrome and pulmonary edema ,PTLD, aseptic meningitis, seizure & infection. it is immunogenic and 50% of the patients will develop antibodies against it after a course of treatment and this has prevent the use of it as a maintenance therapy. it is administered via IV route.
It is no longer used because of life threatening first dose reaction.
ATG is a polyclonal IgG produced from the sera of rabbit or horse, after infusion, ATG reacts against a variety of targets including red blood cells, neutrophils, dendritic cells and platelets in addition to T cell depletion. also it causes rapid expansion of Tregs.
ATG is used for induction therapy and treatment of steroid resistant rejection.
side effects include cytokine release syndrome, infection, malignancy and hematological abnormalities like anaemia, thrombocytopenia & leukopenia.
ATG is given by IV infusion.
References:
Handbook of kidney transplantation by Gabriel M. Danovitch, Sixth Edition
Bamoulid J., Staeck O., Cre´pin Th., Halleck F., et al. Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects. Nephrol Dial Transplant (2017) 32: 1601–1608.
medscape
Mohamad Habli
3 years ago
OKT3 or Muromonab-CD3 is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. In 1986 Muromonab was the first approved monoclonal antibody, by FDA, to be used in humans.
As mentioned is the previous clinical scenario, T lymphocytes activation begins with signal 1 with the binding of TCR/CD3 to antigenic peptides presented by the APC which then triggers the activation in tyrosine phosphorylation of multiple cellular proteins and subsequent activation , proliferation and differentiation of T lymphocytes. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface.
In 2010, Muromonab was withdrawn from the market by the manufacturer because of numerous side effects and available alternatives with better tolerability and less side effects.
Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants. It is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.
The use of OKT3 was associated with several side effects. The first infusion of OKT3 could be associated with activation of T cells with subsequent release of cytokines like tumor necrosis factor and interferon gamma. This cytokine release syndrome is associated with fever, chills, nausea, vomiting, skin manifestations, and could lead to life-threatening conditions . When used, premedication with acetaminophen, diphenhydramine and steroids is needed to minimize the risk of CRS.
Other adverse effects include leucopenia, aseptic meningitis and encephalopathy.
The usual dose is 5 mg administered as an intravenous bolus over 2-4 minutes daily for 10-14 days.
Thymoglobulins
Thymoglobulin acts as a rapid T-cell-depleting agent in both the blood and peripheral lymphoid tissues. The major pathways for T-cell depletion are complement-dependent cell lysis in the blood compartment and apoptotic cell death in the lymphoid tissues. There are 2 forms of antithymoglobulins depending on the origin of antibodies.Thymoglobulin is a polyclonal antibodies that are generated in rabbits and used as immunosuppressive therapy. Although there is no generic formulation, it is commonly referred to as rabbit antithymocyte globulin, or rATG. Another polyclonal antibody, Atgam, is a purified gamma globulin solution. It is obtained by immunization of horses with human thymocytes. Rabbit antithymocyte globulin is more effective than Atgam in lowering the acute rejection rate. That’s why it is commonly used in the induction immunosuppression in high risk patients.
ATG use, as OKT3, can induce cytokine release syndrome, and is associated with an increase in the risk of post-transplant lymphoproliferative disorder. However, this association could be altered with the use of lower doses. Temporary depletion of the T-cell population at the time of the transplant also risks delayed acute rejection, because of delayed rebound activation of T cells. There is also evidence to that inducion immunosuppression with rATG could create conditions in the patient’s immune system favorable to the development of immunological tolerance.
ATG is given intravenously at rate of 1.5 mg/kg in 0.9% NaCl given over 6 – 8 hours in the perioperative period.
A study on the acute steroid-resistant rejection episodes treated with set doses of anti-thymocyte globulin (ATG) or anti-CD3 monoclonal antibody (OKT3), with the monitoring of T lymphocytes showed that administration of ATG and OKT3 is safe and seems effective in treatment of ASRR.
References:
-Midtvedt K, Fauchald P, Lien B, et al. (February 2003). “Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection”. Clinical Transplantation. 17 (1): 69–74.
– Mutschler, Ernst; Gerd Geisslinger; Heyo K. Kroemer; Monika Schäfer-Korting (2001). Arzneimittelwirkungen (in German) (8 ed.).
-Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 937. ISBN 3-8047-1763-2.Smith, S. L. (1996). “Ten years of Orthoclone OKT3 (muromonab-CD3): a review”. Journal of Transplant Coordination. 6 (3): 109–119, quiz 119–
-Abdi, Reza; Spencer Martin; -Steven Gabardi (2009). “Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy” (PDF). Nephrology Rounds. 7 (4)
-Mahmud, Nadim; Dusko Klipa; Nasimul Ahsan (2010). “Antibody immunosuppressive therapy in solid-organ transplant Part 1”. mAbs. 2 (2): 148–156.
-Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006; 355:1967.
-Hardinger KL, Brennan DC, Schnitzler MA. Rabbit antithymocyte globulin is more beneficial in standard kidney than in extended donor recipients. Transplantation 2009; 87:1372.
-Miller JT, Collins CD, Stuckey LJ, et al. Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression. Pharmacotherapy 2009; 29:1166.
-Wiland AM, Fink JC, Weir MR, et al. Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial. Transplantation 2004; 77:422.
-Cassuto JR, Levine MH, Reese PP, et al. The influence of induction therapy for kidney transplantation after a non-renal transplant. Clin J Am Soc Nephrol 2012; 7:158.
In your practice (in your opinion if you are not practising) what are the indications of ATG induction? and what is the dose and the duration of treatment?
1) historical crossmatch positive
2)nil match for HLA A and B antigens
3)deceased donor transplant
4)CDC negative, FCXM positive, DSA negative
5)CDC negative, FCXM positive, DSA positive with MFI <1000,1000-10000(along with desensitization)
6)CDC negative, FCXM negative, DSA positive with MFI <1000,1000-10000(along with desensitization)
dose- (total 3mg/kg)1.5mg/kg each on POD 0 and POD 2.
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?
acute TCMR- no indication
steroid resistant acute TCMR- ATG is used for rejections that do not respond to corticosteroids.
other options- MMF, rituximab, IvIg, plasmapheresis, tacrolimus
recurrent acute cellular rejections- ATG
acute ABMR- when ABMR is associated with severe TCMR ATG could be combined with other treatment modalities.
Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects– Jamal Bamulid et al
mechanism of actionOKT3- is a murine monoclonal antibody against CD3- Rapid (within 1 hour) activation and cytokine release from, all CD3 + cells- Subsequent internalization of the T-cell receptor and T-cell unresponsiveness-Clearance of >90% CD3 cells from the circulation within 24 hours.
Repeated administration is required to maintain CD3 depletion.
ATG-includes antibodies against components of the T-cell receptor (CD3, CD4 and CD8),HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules. Leads to T-cell activation, clearance of T cells from the circulation, inhibition of both co-stimulatory and proliferative signals, and inhibition of cell adhesion and migration.
T-cell depletion following ATG may persist for months or years.
indicationOKT3-treatment of severe or resistant rejection
ATG- as induction therapy in high immunological risk pts, deceased donor transplants, historical crossmatch positive, nil match for HLA A and B antigens, CDC negative, FCXM positive, DSA negative CDC negative, FCXM positive, DSA positive with MFI <1000,1000-10000(along with desensitization) CDC negative, FCXM negative, DSA positive with MFI <1000,1000-10000(along with desensitization) steroid resistant TCMR, severe mixed TCMR and ABMR
side effect OKT3-
anaphylaxis
cytokine release syndrome
diarrhoea and vomiting
dyspnoea and bronchospasm
severe non cardiogenic pulmonary edema
headache
aseptic meningitis
rarely encephalopathy, seizures
increased infections
increase in PTLD by 2-3 fold.
ATG-
anaphylaxis
cytokine release
decreased platelets and leucocytes
increased infections
increase in PTLD
mode of administrationOKT3 – Precautions
• Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
• Ensure that the patient is not fluid overloaded.
• Weight within 1–2kg of dry weight, No pulmonary edema on CXR, and minimal peripheral edema
• Normal BP.
• Pre-medication to be given 30–60 minutes before the first 2 doses of OKT3-
• IV methylprednisolone (250mg if <60kg, 500mg if >60kg)
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Dose
• Following pre-medication, OKT3 is given as an IV bolus of 5mg (2.5mg for children <30kg) into a peripheral vein.
Given daily for 10 days .
Monitoring
Flow cytometry to identify CD3+ cells, If CD3 cells >0.05×10 /L then ↑ dose to 10mg daily
ATG
Precautions
Cytokine release leading to fever and rigors is common after the first one or two doses of any ATG preparation.
• Do not give Thymoglobulin if there is untreated infection, ↓platelets or ↓WCC.
• For the first dose, ensure that the patient is not fluid overloaded.
• Pre-medication to be given 60 minutes before each dose of Thymoglobulin :
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be <0.5mg/ml).
• Thymoglobulin must be given into a central vein
• Following pre-medication, Thymoglobulin is given as an IV infusion over >6 hours (first dose) or >4 hours (subsequent doses).
• decrease the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Monitoring
• Measure CBC daily
• If platelets <75×10 /L → half dose, <50×10 /L → omit
• If WCC <3.0×10 /L → half dose, <2.0×10 /L → omit
• Measurement of CD3 T cells by flow cytometry daily, If CD3 count <0.05×10 /L then no Thymoglobulin is required that day.
Dose
• Induction therapy—6mg/kg, with the first dose of 1.5mg/kg administered intra-operatively, and subsequent doses daily, or on postoperative days 1, 3 and 5 or
3mg/kg with 1.5mg/kg on POD 0 and POD2.
• Rejection therapy—typically 1.5mg/kg daily for 10–14 days, with daily dose determined by monitoring of CBC± CD3 cell count.
OKT3:
Monoclonal Ab ,Blocks CD3 function in T lymphocytes leads to internalization of the T-cell receptor and T-cell unresponsiveness , With Clearance of >90% of CD3 cells from the circulation within 24 hours
Indication:
In induction therapy and in the treatment of acute rejection.
Adverse effects:
Anaphylaxis
Cytokine release syndrome
Increase infections
Increase in post-transplant PTLD
Thymoglobulin: ATG
Mechanism of action
Polyclonal Ab with cytotoxic effect against a variety of T-cell markers leading to depletion of prepheral lymphoctyes and can causes rapid sustained expansion of CD4+, CD25+, FOXP3 T reg cells involved in graft tolerance.
Indication:
Same as OKT3
Adverse effects:
Anaphylaxis with Cytokine release
Decrease WBC and platelet
Increase infections
Increase in PTLD
Thank you Mohamad just please remember as per your last sentence
OKT3 is really not at all safe it is out of use for quite some time. It is included in the discussion just for comparison.
Rabbit Anti-Thymocyte Globulin
Rabbit anti-Thymocyte globulin (rATG) is a polyclonal antibody prepared by injection of a rrabit with human lymphoid tissue (thymocytes or activated human T-cell line ); it has largely replaced eATG ( produced from horses ), which is less potent.
Mechanism of Action
The exact mechanism of action is not fully understood but it contains cyto-toxic antibodies directed against a variety of T-cell markers.
It induce lymphopenia especially T lymphocytes,either by lysis or by removal through reticuloendothelial system.
Of particular importance,Thymoglobulin causes sustained and rapid expansion of CD4+, CD25+, FOXP3+ regulatory T cells that may help in tolerance .its effect may lasts for years . The prolonged immuno-suppressive effect may account for the relative infrequency of
episodes of rejection recurrence.
Dose and Administration
The standard dose of rATG is 1.5 mg/kg given in a course lasting 4 to 10 days.
During induction it is more effective when it is used intra operatively , to reduce the incidence of delayed graft function .
It is given as infusion in 500 ml saline or dextrose given over over 4 to 8 hours into a central vein or arteriovenous fistula.
Patient should be treated by IV premedication consisting of
§ methylprednisolone, 30 mg,given 30 minutes before injection
§ diphenhydramine hydrochloride 50 mg given 30 minutes before injection.
§ Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control.
v Azathioprine, MMF, and sirolimus should generally be discontinued during the course of treatment to avoid exacerbating hematologic side effects.
v Cyclosporine or tacrolimus can be omitted during the course or given in a low dose,
v oral prednisone is replaced by the methylprednisolone given in the premedication.
Adverse Effects
Chills, fever, and arthralgias (common ),
severe first-dose reactions (rare).
Anaphylaxis( occasional) .
Serum sickness (rare). typically presents with diffuse arthralgias, fever, malaise, and rash 1 to 2 weeks following infusion.
Leukopenia occurs in up to half of patients. Which needs dose modification .
The dosed is reduced if leucopenia or thrombocytopenia occur .
If leucopenia occur neupogen can be used .
Absolute lymphocyte count of 0.1% is the target of treatment . Patients who do not respond may require a higher dosage or a prolonged treatment course.
CMV may be a late adverse sequel .its incidence depend on dose and duration of treatment . prophylaxis before, during, and after a course is needed .recipient negative donor positive state is a high risk for CMV infection .
lymphoma is infrequent but a well-recognized complication.Epstein-Barr virus (EBV)negative recipient receiving a graft from an EBV-positive donor appear to be at greatest risk.
Muromonab CD3 (Orthoclone OKT3, Orthoclone, OKT3) is the first monoclonal antibody to become available for therapy in humans. it blocks all cytotoxic T cell function. Clinical trials show that muromonab CD3 is effective in reversing acute renal, and combined kidney- pancreas transplant rejection episodes. It also effective in the treatment of rejections resistant to conventional treatment. It is used only when no other option is available .It is more effective than high-dose corticosteroids in reversing first episodes of acute renal. it appears effective as a prophylactic treatment against acute renal rejection in the immediate post-transplantation period. The development of neutralising antibodies may limit the effectiveness of a second course of muromonab CD3 therapy in some patients.
PharmacologyMuromonab CD3 is a purified murine monoclonal antibody directed against the CD3 antigen, which is found on all mature human T cells. It is an IgG2a immunoglobulin which binds to one of the subunits of the CD3 complex, a part of the T cell receptor, thereby blocking function of the adjacent Ti complex involved in recognition of foreign antigens by the T cell.Within minutes of intravenous muromonab CD3 administration there is a rapid clearance of CD3+ cells from circulation which is complete within 1 hour. The T cells are believed to be, at least in part, opsonised and removed from circulation by the reticuloendothelial system. muromonab CD3 blocks all T cell function including both the induction and effector phases of cell-mediated lympholysis and T cell proliferative responses to both class I and II major histocompatibility complex antigens.
Mean trough steady-state plasma concentrations of muromonab CD3 are about 0.9 mg/L after about 2 or 3 once-daily intravenous doses of muromonab CD3 5mg. This plasma concentration is generally believed to be adequate to block cytotoxic T cell function based on in vitro studies.
Side EffectsThe first doses of muromonab CD3 are associated with a number of side effects which can be frequent and inconvenient or, more rarely, severe and life-threatening. Most side effects occur within 45 to 60 minutes of administration and last several hours .
The most frequent effect is a ‘flu-like’ complex consisting of fever and chills in most patients (> 50%) followed by dyspnoea, tremor, chest pain and tightness, wheezing, diarrhoea, nausea and vomiting in about 10 to 20% of patients, and infrequently tachycardia, hypertension, hypotension, joint pain, pruritus and rash. More severe first-dose effects are aseptic meningitis and pulmonary oedema.
Dosage and AdministrationThe recommended adult dose of muromonab CD3 is 5mg administered by intravenous bolus injection once daily for 10 to 14 days. Some patients require as much as 10mg to achieve T cell depletion. Before treatment patients with temperature exceeding 37.8°C should receive antipyretics. T
Intravenous methylprednisolone sodium succinate 1.0 mg/kg given just before muromonab CD3 administration and intravenous hydrocortisone sodium succinate 100mg 30 minutes after muromonab CD3 administration decreases the incidence and severity of first-dose reactions. Paracetamol (acetaminophen) and antihistamines can be given concomitantly with muromonab CD3 to reduce early reactions.
Norman DJ. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20. doi: 10.1097/00007691-199512000-00012. PMID: 8588230
OKT3(Muromonab CD3,Orthoclone):
Mechanism of action:
It is the first approved murine mAb for human use 1986
The biologic target of OKT-3 is the ε chain of CD-3 subunit of the CD3 TCR-associated complex
It initially activates T cells, which leads to a cytokine release syndrome. Then it prevents activation and depletes CD4 and CD8 T cells.
Indications:
It is used as an induction agent for high-risk patients.
To treat steroid resistant acute rejection in solid organ transplantation.
Side effects:
Cytokine release phenomenon with the first few infusions (due to release of TNF-α and IL-2) characterized by symptoms like headache, nausea, fever, fatigue, myalgia and may lead to life threatening situation(apnea, flash pulmonary edema and cardiac arrest)
Nonspecific T-cell depletion that can result in over-immunosuppression, with increased risk of infections ( bacterial, viral and opportunistic).and PTLD
Neurological side effects (encephalopathy and aseptic meningitis).
Tachyphylaxis was reported with repeated administration
Xenosensitization occurs If repeated doses of OKT-3 treatment are required as the agent is of murine origin and can trigger the production of human anti-mouse antibodies (HAMA)
In view of these side effects and the availability of alternative therapies, OKT3 was withdrawn from the market in 2010
Mode of administration:
OKT-3 can be administered through a peripheral vein but it requires filtration before administration of the dose to remove particulate matter in the preparation.
It requires concomitant administration of antihistamines, acetaminophen, and steroids to reduce the incidence of the first-dose response.
It has 100% bioavailability
The usual course of therapy is 7 to 10 days, but is dependent on whether the agent is being used as an induction agent or to treat steroid-resistant rejection.
The adult dose is 3 – 5 mg/kg/day
Anti-thymocyte globulin: ATG is a polyclonal IgG-antibody preparation produced by immunizing horses or rabbits with human thymocytes and immunoglobulins against thymocytes are isolated and subjected to a number of purification processes
Mechanism of action :
It targets a large variety of immune cell surface proteins, so it does not only deplete T-cells but also down regulates the molecules that control T cell activation. Moreover, it interferes with the function of a number of different immune effector cells, including B cells, dendritic cells, natural killer (NK) T cells, and Tregs
Its efficacy as an immunosuppressive agent is primarily through rapid induced apoptosis of CD3+ T cells. Recovery of peripheral T-cell counts occur gradually after cessation of thymoglobulin treatment (>50% of initial lymphocyte count at 3 months).
Indications :
Thymoglobulin is indicated in induction therapy immunologically high-risk patients and those at increased risk of DGF by reducing the ischemia reperfusion injury.
It can be used in TCMR including vascular lesions and as a rescue therapy in steroid resistant acute rejection episodes
ATG is not a first-line treatment for ABMR but might be considered in patients with TCMR-associated acute ABMR
Side effects :
1. Anaphylaxis, with a drop in blood pressure, respiratory distress, fever and urticaria may appear during or just after the infusion. Other hypersensitivity reactions include rigors, arthralgia, erythema and pruritic skin eruptions
2. Increase risk of infections especially CMV and PTLD
3. Other side effects include thrombocytopenia ,neutropenia and serum sickness
Mode of administration and dosage :
Infused through a central line but can also be given in peripheral line.
To reduce severity of infusion related reactions, pre-medicate with corticosteroids, acetaminophen, and antihistamines 1 hour prior to infusion and give the first dose over at least 6 hours; subsequent doses may be infused over at least 4 hours.
Start prophylaxis against antifungal infection(nystatin), Pneumocystis jiroveci infection(Co-trimoxazole) for 3 months and CVM infection with (valgancyclovir) for 6-12 months
Induction doses have ranged from 1–6/kg/dose over 1–10 days with a more typical regimen of 1.5 mg/kg for 3–5 days starting from day zero.
For acute rejection ATG is given at dose of 1.5 mg/kg/day IV for 7-14 days
References
1.Sgro, C. (1995-12-20). “Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review”. Toxicology. Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology. 105 (1): 23–29
2.Simon steddon,Neil Ashman. Handbook of Nephrology and Hypertension. second addition
OKT3-(Muromonab-CD3):
Monoclonal antibody acts against CD3 receptor which On T Lymphocytes.
The Side effects of Muromonab-CD3 is variable which includes pulmonary oedema, gastrointestinal and neurological abnormalities (7). The feedback of use Murmonab-CD3 as induction therapy among transplant recipient
There is distrust about its uses and effects on kidney transplantation
It is found that the use of the OKT3 is masked by other immunosuppressive agents .
Recently it was withdrawn from the US markets(7).
Antithymocyte globulin
Polyclonal antibody which has 2 forms either rabbits (rATG) or horses (ATGAM) .
Its action is not appear clear but it lysis the complement of various immunocompetent of the cell .
The immune system took time to recover especially in old ages (8).
The side effects of Antithymocyte globulin
Sever first dose reaction ( cytokine release syndrome):chills, fever arthralgia and hypotension
Thrombophlebitis and peripheral vein thrombosis Thrombocytopenia and leukopenia Developing infection especially cytomegalovirus
Anaphylaxis Post-transplantation lymphoproliferative disease(PTLD)
OKT3 blocks both the generation and function of cytotoxic T cells. After an initial dose
of OKT3, T cells virtually disappear from the circulation within minutes to hours. During
treatment with OKT3, T cells .
OkT 3 used to treat rejection.
Side effect associate associate. With cytokine release .Increase risk of infection.
ATG mechanism of action:
Binding to antibodies and cytokines.
nhibition of compliments.
Bindings FC portion and induce FC inflammation.
Side effect of ATG:
fever,
anaphylactoid reactions.
headaches (including aseptic meningitis),
thrombotic complications (including myocardial infarction),
acute kidney injury.
ATG used in induction therapy and treatment of rejection..
References :
DJ Norman .Mechanisms of action and overview of OKT3. Drug Monit. 1995
Dec;17(6):615-20.
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action
ATG is depleting polyclonal antibodies: polyclonal means multiple b cell colonies are involved in its formation as multiple antigens are used (cd2,3,4,8,18)and injected in animal (rabbit and horse) during its manufacture
ATG cause both bcell and Tcell depletion
Okt3 is monoclonal antibodies:single colony of b cell is involved in its manufacture as single antigen is used cd3 causing only tcell depletion
According to indication
ATG: Is used in 1) induction therapy: used preoperative or intraoperative in moderate to high risk patient with dose around 3mg/kg in divided doses
2) used in treatment of both tcell mediated rejection (when resistant to steroids or score 2a or more) or ABMR or mixed rejection in dosing 5-9mg/kg
Okt3:the original use was for treatment rejection but it was used in some pediatric centers for induction
According to side effect
ATG: causes serum sickness, cytokines release syndrome, anaphylaxis reaction, pancytopenia, increase risk of infection specially CMV virus and PNC bacterial infection and increase risk of PTLD
OKT3: cytokines storm, anaphylaxis shock, CMV infection and PTLD
Regarding mode of administration?
ATG : used as infusion over 6h in large veins proceeded by methylprednisolone and acetaminophen if mild reaction happened it can hold then continue on slow rate but if sever reaction happened it should be discontinued.also cbc showed be followed
If plt count below 50000 or TLC below 2000 next dose should be held but if plt count ()75000 and 50000 or TLC ()3000 and 2000 next dose should be halved
Okt3: it given as a bolus so its can’t withdrawal or decreasing infusion rate as ATG
REFERANCES
1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-203
2. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
3. Kutzler HL, Ye X, Rochon C, Martin ST. Administration of antithymocyte globulin (rabbit) to treat a severe, mixed rejection episode in a pregnant renal transplant recipient. Pharmacotherapy. 2016;36(4):e18‐e22.
4. Adair JC, Woodley SL, O’Connell JB, et al. Aseptic Meningitis following Cardiac Transplantation: Clinical Characteristics and Relationship to Immunosuppressive Regimen. NeuChatenoud L, Legendre C, Ferran C, et al. Corticosteroid Inhibition of the OKT3 – Induced Cytokine-Related Syndrome – Dosage and Kinetics Prerequisites. Transplantation 51:334–338, 1991.
5. Cockfield SM, Preiksaitis J, Harvey E, Jones C, Herbert D, Keown P, and Halloran PF, et al. Is Sequential Use of ALG and OKT3 in Renal Transplants Associated with an Increased Incidence of Fulminant Post Transplant Lymphoproliferative Disorders? Transplant. Proc. 23:1106–1107, 1991.rology 41:249–252, 1991.
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action, indication, side effect and mode of administration?
Mechanism of action:
OKT3: Muromonab or OKT3 is a an anti CD3 monoclonal antibody. It is directed against the e subunit of CD3 closely associated with T cell receptor on T cell, binding to the T cell and leading to complement activation with T cell apoptosis.
Thymoglobulin: It is rabbit Anti Thymocyte Globulin (rATG), a purified polyclonal antibody. It mainly targets the pre-activated, non-cycling memory lymphocytes. Its main action is T lymphocyte depletion by complement dependent cell lysis. It also binds with B cell surface proteins including CD30, CD38, CD80 and CD95 leading to apoptosis and depletion of B cells.
Indication: In transplantation
OKT3: OKT3 has been used as:
1) Treatment of acute rejection
2) Prevention of acute rejection: Induction therapy
In non-transplant setting, OKT3 has been used in T cell Acute lymphocytic Leukemia
Thymoglobulin: It has been used as:
1) Prevention of acute rejection: Induction therapy for high immunological risk patients.
2) Treatment of acute rejection: For acute T cell mediated rejection or mixed rejections.
Side effect: The side-effects are:
OKT3:
1) Cytokine release phenomenon: This happens due to initial activation of T cells releasing TNF alfa and interleukin 2. It presents with headache, nausea, fever, fatigue, body-aches, shortness of breath, pulmonary edema or cardiac arrest.
2) Non-specific T cell depletion: Leading to over-immunosuppression, increased risk of infections and PTLD.
3) Leukopenia
4) Neurological: Encephalopathy, aseptic meningitis, cerebral edema.
5) Tachyphylaxis: with repeated doses
6) Anaphylactic reactions.
Thymoglobulin:
1) Cytokine release phenomenon: This happens due to initial activation of T cells releasing TNF alfa and interleukin 2. It presents with headache, nausea, fever, fatigue, body-aches, shortness of breath, pulmonary edema or cardiac arrest.
2) Leukopenia, Thrombocytopenia
3) Abdominal pain, nausea
4) Infections: UTI, CMV
5) PTLD
6) High blood pressure or hypotension
7) hyperkalemia
Mode of administration:
OKT3: The dose of OKT3 is 5 mg/kg/day intravenous fast over less than one minute. for 7-10 days. It can be administered via a peripheral vein. Premedication with IV methylprednisolone, paracetamol and anti-histamines is warranted to decrease the incidence and severity of first dose reactions.
Thymoglobulin: Dose is 1.5 mg/kg/day for 4-7 days as induction therapy and 7-10 as treatment for rejection. It is administered as IV infusion over 4-6 hours through a central line after premedication with IV methylprednisolone, paracetamol and anti-histamines to prevent infusion related reactions.
Which one you prefer to give?
We use rATG (Thymoglobulin). OKT3 is not available. Even if OKT3 were available, rATG has a better safety-profile than OKT3 and hence better to use.
OKT3:
mechanism of action:Bind to TCR-CD3 , leading to clearance of TCR and hence T cell apoptosis.
indication
Acute sterid rejection kidney transplantation
side effect
Infusion reactions, chills, urticaria, flash pulmonary edema.
mode of administration
Thymoglobulin::mechanism of action:polyclonal antibody acting on several site including b and t cells, natural killer cell but mainly act though CD3 t cell depletion
indication
not only treatment of rejection as okt3 , but also may be used for prevention of such rejection.
side effect
hypo- and hypertension , tachycardia, abdominal pain, constipation, Acne
mode of administration
OKT3 is a monoclonal AB which inhibits signal 1through its action against CD3,ATG is polyclonal AB ;a lymphocyte depleting agent.
OKT3 was used in treatment and prevention of acute transplant rejection ;withdrawn from market.
Side effects of OKT3 : some include cytokine syndrome ,leucopenia and CNS side effects.
ATG
lymphocyte depleting through complement dependent cell lysis.
used as induction therapy in addition to conventional immunosuppression specially in high risk patients.
Some of its side effects include increased infection &malignancy ,allergic and hematological side effects.
ATG is the currently used agent
rThymoglobulin ( rabbit ATG ) .
Is a polyclonal antibody , It has replaced equine ATG .
The exact mechanism of action of ATG is not fully understood but it is believed to be directed against various T cell markers leading to cell lysis.
Uses :
As induction therapy
Treatment of steroid resistant cellular rejection
Usual dose is 1.5 mg /kg for 4 to 10 days
Side effects include:
Hypersensitivity reactions
Leukopenia and thrombocytopenia
Infections
Lymphoma
OKT3
is a monoclonal antibody directed against CD3 ,which is a molecule found only on mature T cells .
CD3 is located very near to TCR for antigens ,OKT3 blocks both the generation and function of cytotoxic T cells.The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3
OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients.
It’s only given through IV route.
Adverse effects include:
*Serious anaphylaxis
* cytokine release syndrome
* Aseptic meningitis and encephalopathy have been observed.
We use ATG , No OKT3
OKT3 act as a monoclonal antibody against CD3 and inhibits signal one. Thymoglobulin is a polyclonal antibody which is provided by immunization of rabbits with human lymphoid tissue and thymocytes are used for it. OKT3 had potent life-threatening first- dose reactions such as chills and fever and respiratory symptoms caused by inflammatory mediators. Nowadays it is replaced by thymoglobulin. Thymoglobulin contains antibody against different kinds of T cell markers and causes depletion of peripheral lymphocytes and can cause prolonged lymphopenia .It is used for induction of immunosuppression and treatment of refractory T cell rejection. Other side effects is chills and fever with lower intensity than OKT3 .To prevent its reaction side effects, premedication with acetaminophen, antihistamines and corticosteroid is considered. Other side effects include serum sickness, thrombocytopenia and leukopenia which need dose reduction or sometimes stopping the drug. CMV infection is a well-known side effect that necessitated CMV prophylaxis while they are administrated. OKT3 was administer by IV bolus infusion. Recently oral administration of humanized anti-CD3 monoclonal Ab is used for treatment of non- alcoholic steatohepatitis (NASH) .Thymoglobulin is administered by IV route. Initially it was recommended by central line but recently peripheral IV administration was shown to be safe by using premedication over 6 hours.
OKT3
Mechanism of action :
When administered, OKT3 cause rapid activation and cytokines release from all CD3+cells
Subsequent internalization of the T-cell receptor and T-cell unresponsiveness.
Clearance of >90% of CD3 cells from the circulation within 24 hours
Indication:
as induction therapy in renal transplantation and in the treatment of acute rejection.
Adverse effects:
Anaphylaxis
Cytokine release syndrome
Increase infections
Increase in post-transplant PTLD
Administration of OKT3:
Premedication (IV methyl prednisolone,IV H1 antagonist ,paracetamol PO)
Dose:
given as an IV bolus of 5 mg (2.5 mg for children <30 kg ) into peripheral vein .
give daily for 10 days.
Thymoglobulin:
Mechanism of action
ATG administration has multiple effects including T-cell activation,leading to cytokines release , clearance of T cells from the circulation,inhibition of both co-stimulatory and proliferative signals and inhibition of cell adhesion and migration.
Indication:
Used in induction therapy for renal transplantation and for acute kidney rejection.
Adverse effects:
Anaphylaxis
Cytokine release
Decrease WBC and platelet
Increase infections
Increase in PTLD
Serum sickness
Administration of ATG :
Test dose:
5 mg in 100 ml 0.9%NaCl over 30 minutes into a peripheral vein is given without premedication.
Thymoglobulin is usually diluted into 500 ml 0.9 NaCl (the final concentration should be 6 hours (first dose ) or > 4 hours ( subsequent doses)
ATG mostly used due to its less side effects
OKT3 removed from the market
OKT3 vs Thymoblobulin :
Oxford hand book of nephrology & hypertension ,second edition.
Thymoglobulins are anti lymphocyte polyclonal Ab produced by activating the immune system of either rabbit or horse by human lymphoid tissue.
OkT 3 orthoclone is a monoclonal Ab muromonab-CD3.
Mechanism of action of thymoglobulins:
Contains cytotoxic Ab directed against T cells causing decrease in their number in peripheral blood by T cells lyses by reticuloendothelial system and masked their surface Ag .
Thymoglobulin also cause expansion of FOXP3+ regulatory T cells which plays crucial role in immune response balance and decrease risk of graft rejection and loss it causes prolonged lymphopenia and CD4 inhibition which may prolonged to several years thus help preventing rejection episodes.
Administration:
1.5 mg /kg dose diluted in 500ccN/S or dextrose within 4-8 hrs in large central veins to avoid it’s thrombophlebitic effects, vital signs should be monitored regularly and closely,premedications should be given prior to thymoglobulins administration to decrease side effects.
Side effects:
Mainly due to administration of foreign protein causing anaphylaxis like reaction like chills,fever,generalised weakness,rash and may continue over 1-2 week after the dose ,this effect can be minimized by using pre medications before treatment like acetaminophen, methylprednisolone ,diphenhydramine and hydrocortisone.
Blood count monitoring is necessary because it’s leukopenic effect which needs to reduce to half dose or stop the infusion and if it’s sever neupogen may be used .
OKT 3 muromonab CD3
Is the first monoclonal Ab that had been used in clinical practice as human immunosuppressant by it’s effects on CD3 receptors on T cells surface used for acute cellular rejection ,it’s IgG 29 Ab binds to TCR ,CD3 complex leading to T cells apoptosis and prevent graft rejection .
Administration
The dosage of OKT3 is 5mg/day in bolus IV injection can be given on peripheral veins for less than 1 minute for 10-14 days ,premedications also must be given to decrease or prevent drug side effects.
Side effects
After administration of OKT 3 this will release cytokines like TNF and interferon gamma which are responsible for it’s side effects that are known as (cytokines release syndrom) like skin reaction fatigue, fever,rigor GI symptoms,and even life threatening conditions like pulmonary oedema apnea and even cardiac arrest ,these all can be avoided by using acetaminophen, methylprednisolone and diphenhydramine as pre medications. Other side effect is leukopenia and this will increase risk of infection ,aseptic meningitis encephalopathy and malignancies..
Both these drugs are used to prevent acute cellular rejection so they can be used in induction and in treatment of cellular rejection.
Thymoglobulins can be given also in AMR due its effect on CD4+T cells and B cells interaction so it cause B cells apoptosis and AlloAb production modulation so it cause decrease B Cells but it’s action tends to be more effective when it used with rituximab (not used thymoglobulins as monotherapy in AMR patients).
1- OKT3
a- Mechanism of action :
Monoclonal Ab ,Blocks CD3 function in T lymphocytes , required for Ag recognition & signal transduction)
b- Indications :Treatment of acute kidney allograft rejection
c- S.E:
1- Cytokine Release Syndrome
2- Neurological complications : headache , cerebral edema Seizures, encephalopathy, , aseptic meningitis.
3- Anaphylactic Reactions during administration
4- Complications related to immunesuppression effects as increase risk of infections and malignancy.
d- administration
1- Premedication with 1 mg /Kg methyl prednisolone
2- Filter OKT3 with a low protein-binding 0.22 micron filter
3- Then administer OKT3 as IV push undiluted Followed by hydrocortisone 50 – 100 mg Iv .
ATG
a- Mechanism of action : Polyclonal Ab with
1- cytotoxic effect against a variety of T-cell markers leading to depletion of prepheral lymphoctyes
2- causes rapid sustained expansion of CD4+, CD25+, FOXP3 T reg cells involved in graft tolerance.
b- Indications :
1- Induction therapy for high risk patients
2- Treatment of acute graft rejection
c- S.E:
Same as OKT3
1- Hematological effects as leukopenia (including lymphopenia and neutropenia) , thrombocytopenia.
d- administration a;
1- Premedicate recommended with corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion.
2- Slow infusion over 4-6 h diluted in either 0.9 normal saline or 5% dextrose. Each vial should be diluted in 50 mL of infusion solution
3- Infuse IV through 0.22 micron filter into high-flow vein.
4- Decrease the dose by 50% if WBC is ≥2000 but ≤3000/mm3 or platelet count is ≥50,000 but ≤75,000/m3. Consider drug discontinuance if WBC <2000/mm3 or platelet count <50,000/mm3.
OKT 3
OKT3 is a murine monoclonal antibody of the immunoglobulin IgG2a isotype. The target of OKT3, CD3, that is part of a multimolecular complex found only on mature T cells and medullary thymocytes. This complex is uniquely situated next to the T-cell receptor for antigen. An interaction between T cells, OKT3, and monocytes causes T-cell activation
Because of the unique association between the antigen receptor and CD3, antibodies that react with CD3 block T-cell receptor function and vice versa. Thus, OKT3 blocks both the generation and function of cytotoxic T cells.
Indication
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients.
Orthoclone OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients.
Side effects
Especially during the first infusion, the binding of muromonab-CD3 to CD3 can activate T cells to release cytokines ; cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea, and could lead to life-threatening conditions like apnoea, cardiac arrest, and flash pulmonary edema.[7] To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone), acetaminophen, and diphenhydramine are given before the infusion.
Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies. Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation.
Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti-mouse antibodies in the patient, which accelerates elimination of the drug. It can also lead to an anaphylactic reaction against the mouse protein, which may be difficult to distinguish from a CRS.
Mode of Administration
Give IV push over <1 min undiluted
Do not give IM
Methylprednisolone sodium succinate 1 mg/kg IV given prior to first muromonab-CD3 administration, & IV hydrocortisone sodium succinate 50-100 mg, given 30 min after administration are strongly recommended to decrease the incidence of reaction to the first dose
Filter each dose through a low protein-binding 0.22 micron filter before administration
Pt temperature should not exceed 37.8°C (100°F) at time of administration
antithymocyte globulin
Polyclonal antibodies against human lymphoid tissue. Currently, two ATG preparations are available. Antithymocyte globulin equine (eATG) is a purified, concentrated and sterilized antibody preparation derived from the hyperimmune serum of horses.
Antithymocyte globulin rabbit (rATG) is also a cytolytic polyclonal antibody preparation . It is a purified and pasteurized preparation of gamma immunoglobulin obtained by immunizing rabbits with human thymocytes.
Equine ATG contains antibodies against several T-cell surface markers and after binding to these markers, eATG promotes T-cell depletion by either opsonization and complement-mediated lysis or clearance into the reticuloendothelial system. Cell recovery after depletion with eATG may take several months. Overall, this agent reduces the number of lymphocytes in the peripheral circulation, as well as in the thymus and spleen.
rATG induces immunosuppression in vivo include T-cell clearance from the circulation and modulation of T-cell activation, homing and cytotoxic activities. In vitro, rATG mediates T-cell suppressive effects via inhibition of proliferative responses to several mitogens. rATG is thought to induce T-cell depletion and modulation by a variety of methods, including Fc receptor-mediated complement-dependent lysis, opsonization and phagocytosis by macrophages, and immunomodulation leading to long-term depletion via apoptosis and antibodydependent cell-mediated cytotoxicity. Immune reconstitution may take several months following a course of rATG.
Indications
– the prophylaxis and treatment of acute rejection in patients receiving a kidney transplant in conjunction with concomitant immunosuppression
– Aplastic Anemia
– Myelodysplastic Syndrome
– prevention of graft vs host disease
Side effects
Abdominal pain and other GI symptoms, Asthenia, Chills, Diarrhea, Dyspnea, Fever Headache, HTN, Hyperkalemia, Infection, Leukopenia, Malaise, Peripheral edema, Tachycardia, Thrombocytopenia (37%)
Administration
The standard induction therapy dosing strategy for eATG is 10–30 mg/kg/day IV for 7–14 days. The first dose usually begins shortly before or after transplantation. However, the difficult outpatient administration and high cost of this agent make this prolonged course difficult in many instances. A shorter course of therapy is often used to counter these issues and consists of dosing eATG at 15 mg/kg/day for 7–10 days, stopping once the maintenance immunosuppressive regimen is optimized
Rabbit ATG is not FDA approved for induction therapy; however, many in the transplant community routinely use this antibody for induction therapy. When used in this capacity, rATG has been dosed at 1–4 mg/kg/day and is usually administered for 3–10 days after transplantation. The most common dosing schedule for this agent is four doses of 1.5 mg/kg/day, resulting in a total dosage of 6 mg/kg over the course of the therapy
IV Preparation
Aseptically reconstitute required number of vials with 5 mL supplied diluent (SWI) immediately before use Gently rotate vials to dissolve particulate matters if any; discard if particulate matters persist
Transfer all reconstituted drug into infusion bag containing saline or dextrose, invert bag to mix
Recommended volume: 50 mL of infusion solution per vial (total volume between 50-500 mL)
Premedicate recommended with corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion; may reduce the incidence and intensity of infusion-associated reactions
Infuse IV through 0.22 micron filter into high-flow vein
Infuse first dose over at least 6 hr and subsequent doses over at least 4 hr
OkT3 is a monoclonal antibody specific for CD3 antigen which expressed in all T cells, administered as IV bolus of 5 mg daily for 10 days,has very rapid action within one hour by activation and release of cytokines from CD3 cells; clearance of more than 90% of CD3 within 24 hours. Adverse effect include anaphylaxis and cytokine release syndrome.
Antithymocyte globulin is apolyclonal T cell depleting antibodies,it works against of CD3,CD4 and CD8. The mechanism of action by T cell activation, cytokine release, clearance of T cells from circulation,inhibition of both co stimulatory and proliferative signals,it have some activity to suppress B-cell and plasma cell. Mode of Administration is IV of dose 1.5mg /kg for 4 days (total dose of 6mg),first dose start intraoperative .side effects is cytokine release syndrome , serum sickness and long standing lymphocytes depletion for 6 months .
ATG is preferred than OKT3 due it is less side effects and potent action
Dear All
Is any one of you still using OKT3 in his centre?
Feel free to say yes or no. It is just a screening question
No, we don’t
Dear Dr Ahmed,
We are not using OKT3 in induction or treatment of rejection.
No one use it in Sudan transplant centers
No sure, its not avilable in market
No
In sudan.NO.
Only rATG is available in Turkey (ATG FRESENIUS)
No ,we don’t use OKT3
we are not using it
OKT 3 :
ATG :
Thymoglobulin
Mechanism of action :
it is polyclonal antibodies contain cytotoxic antibodies directed against a variety of T cell markers lead to depletion of peripheral blood lymphocytes
causes sustained and rapid expansion of CD4+,CD25+,FOXP3+ regulatory T cells that play an important role in maintaining immune homeostasis and limiting antigraft immunity.
Indication:
used for induction therapy
prevent and treat acute rejection and increase graft survival in solid organ transplantation , especially kidney, liver, pancreas, and heart transplantation.
Mode of administration:
dose 1.5 mg/kg given in course lasting 4 to 10 days
intravenous infusion in 500 ml dextrose or saline over 4 to 8 hours with intravenous premedication 30 minute before injection by methylprednisolone 30 mg.
Side effects:
Chills,fever and arthralgia , occasional cases of anaphylaxis
thrombocytopenia , leukopenia with the need of reduction or stopping of drug
infection : CMV very common
using repeated courses of the drug is associated with fulminant and rapidly fatal B cell lymphoma
OKT3
Mechanism of action:
it is lymphocyte depleting monoclonal antibody react with human T cells by binding to one of the 20-KDa subunits of the CD3 complex ( the intrinsic part of the T cell receptor )
with deactivation of the CD3 complex and endocytosis of T cell receptor after that T cell will removed from circulation
Depletion of T cells with surface markers CD4,CD8,CD11
Block function of killer T cells
Indication:
induction therapy but because life threatening first dose reaction it replaced by less toxic thymoglobulin ( similar effect)
used when thymoglobulin is contraindicated due to leukopenia or thrombocytopenia
Mode of administration:
5 mg intravenous bolus through Millipore filter daily for 10 days
Side effects ;
infection and lymphoma risk are similar to thymoglobulin
severe life threatening adverse reactions may occur during the first days of administration
rapidly developing life threatening noncardiogenic pulmonary edema if the patient over his dry weight
neurological complication varying from mild headache to severe encephalopathy
References
Handbook of Kidney Transplantation . Fifth Edition
Okt3
Is monoclonal antibody, of IgG isotype, directed against CD3 ,which is a molecule found only on mature T cells and thymocytes .
CD3 is located very near to TCR for antigens , it was found that any antibody that blocks CD3 ,precent T cells from interactions with antigens
OKT3 blocks both the generation and function of cytotoxic T cells.
The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3
OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients.
Is only given through IV route .
Orthoclone OKT3 should not be given to patients who:
are hypersensitive to this or any other product of murine origin.
have anti-mouse antibody titers ≥1:1000.
are in (uncompensated) heart failure or in fluid overload, as evidenced by chest X-ray or a greater than 3 percent weight gain within the week prior to planned Orthoclone OKT3 administration.
uncontrolled hypertension.
history of seizures, or are predisposed to seizures.
pregnant, or who are breast-feeding.
Adverse effects include
*Serious anaphylaxis which may be life threatening
* clinical release syndrome
*Neurological side effects like aseptic meningitis and encephalopathy have been observed.
Thymoglobulin ( rabbit ATG ) .
Is a polyclonal antibody, produced by injecting rabbits with human thymocytes inducing immune response, and obtained rabbit s serum to get the Immunoglobulins .
It has replaced equine ATG .
Exact mechanism of action of ATG is not fully understood but it is believed to be directed against various T cell markers leading to cell lysis .
It also causes expansion of CD4 , CD25 foxp3 and regulatory T cells which plays an important role in managing rejections .
Uses :
As induction therapy
Treatment of steroid resistant cellular rejection
Usual dose is 1.5 mg /kg for 4 to 10 days
Side effects include
Sever 1st dose reactions
Leukopenia and thrombocytopenia
Infections including cmv
Lymphoma
Given on 500 ml dextrose 5 % , over 4 to 8 hours ,
Pre medications as antihistamines, paracetamol, hydrocortisone should be given
Handbook of clinical transplantation
Gabriel M.Danovitch
OKT3 which is a murine monoclonal antibody of immunoglobulin IgG2 isotype targets CD3. It blocks both generation and functşon of cytotoxic T cells. It is not widely used because of side effects and the formation of anti-OKT3 antibodies. It has a high incidence of first use side effects related to cytokine storm manifested as fever and chills etc.
On the other hand, thyroglobulin is safer somehow
It has different formulations like höse or rabbet derived. The most widely used is rATG (rabbit ATG).
ATG is thought to have an effect on T, B, and plasma cells. It depletes T cells within a short time by complement-dependent cell lysis. T cell modulation is another probable mechanism of action.
— Treatment with rATG down-modulates the expression of several molecules that control T-cell activation, including the T-cell receptor (TCR)/CD3 complex, CD2, CD4, CD5, CD6, and CD8
— rATG contains antibodies that can bind syndecan (CD138), a plasma-cell-specific molecule
— . rATG is thought to bind with numerous B-cell surface proteins like CD30, CD38, CD95, CD80, and HLA-DR
Both are indicated for transplant immunosuppression induction as well as acute rejection
https://www.uptodate.com/contents/overview-of-immunosuppressive-agents-used-for-prevention-and-treatment-of-graft-versus-host-disease?search=thymoglobuline§ionRank=1&usage_type=default&anchor=H16&source=machineLearning&selectedTitle=3~49&display_rank=2#H16
Mechanisms of action and overview of OKT3 DOI: 10.1097/00007691-199512000-00012
https://www.karger.com/Article/Pdf/351643
ATG is a mixture of non-specific anti-lymphocyte immunoglobulins targeting not only T cell subsets but also several other immune and non-immune cells.
It has the capacity to deplete T and B cells, to inhibit B and T cell cooperation as well as leucocyte adhesion and to induce certain ‘tolerogenic’ regulatory T cell and dendritic cell (DC) populations.
addition to T-cell depletion, ATG may also result in less T cell activation by the downregulation of molecules that control T cell activation, such as the TCR/CD3 complex, CD2, CD4, CD5, CD6 and CD8.
ATG could act on leucocyte adhesion through downregulation of the cell surface expression of several integrins and intercellular adhesion molecules (e.g. ICAM-1, VCAM, PECAM, CD11b and CD62e) .
MECHANISM OF ACTION OF ATG
ATG is polyclonal immunoglobulin G (IgG) fractions purified from sera of rabbits or horses previously immunized with human lymphocytes.
The sources of lymphocytes are human spleen, blood, thymus or lymphoblastic lineages. After purification, polyclonal cytotoxic antibodies are isolated and able to target numerous immune cell clusters of differentiation and membranous antigens (e.g. CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, HLA-DR, HLA type I etc.).
After infusion, ATG induces immediate immune cell depletion, particularly T lymphocyte depletion, through four known mechanisms :
1 The antibody-dependent cell cytotoxicity pathway is the main mechanism and is the consequence of fixation of the polyclonal antibodies on its specific antigens, while the Fc part of the antibodies are recruiting Fcγ receptor cytotoxic cells [macrophages and natural killer (NK) cells].
2The complement-dependent cell cytotoxicity is dose dependent and related only to those antibodies that are able to fix complement C1q with their Fc part.
3 The opsonization process involves phagocytosis of antibody-recovered T lymphocytes by the reticulo-endothelial network.
4 The activation-induced cell death pathway occurs through the antibody-induced and cytokine-mediated upregulation of CD178 (CD95-L) expression by resting T cells. The Fas-Fas ligand pathway activation induces T lymphocytes apoptosis.
INDICATIONS FOR ATG
1 ATG as prophylactic induction therapy in solid organ transplantation
Induction results in initially lower graft rejection rates , allowing early steroid withdrawal and hospital discharge.
Eventually, ‘mild’ rejections, which are easy to treat, and steroid-resistant rejections in highly immunized patients are prevented, while rejections with inferior outcomes such as humoral rejections are less well prevented,
2 Treatment of acute TCMR
In meta analysis puplished 2006 monoclonal and polyclonal antibody therapy were better than steroids in reversing ongoing rejection and preventing graft loss whether death-censored or including death with a functioning graft . There was no difference in preventing subsequent rejection at 1 year.
ATG has been used as a first-line therapy for TCMR, in particular, those with severe acute TCMR including vascular lesions (≥Banff II categories) and as rescue therapy for steroid-resistant acute TCMR.
Current KDIGO guidelines recommend corticosteroids for the initial treatment of acute cellular rejection (1D) and suggest adding or restoring maintenance prednisone in patients not on steroids who have a rejection episode (2D) .
3 Steroid-resistant acute rejection
evidence-based data are scarce, old and do not allow using ATG as a first-line therapy in mild to moderate first acute rejection. Current KDIGO guidelines suggest using lymphocyte-depleting antibodies or OKT3 for acute cellular rejections that do not respond to corticosteroids and for recurrent acute cellular rejections (2C).
4 Acute ABMR
One retrospective study has evaluated seven high immunological risk patients who developed early post-transplant acute ABMR [60]. The treatment consisted of an ATG-based regimen (mean dose 0.79 mg/kg/day for a median of 6 days), including steroid pulse therapy and plasma exchange. The authors showed a significant decrease in post-treatment creatinine with an improvement in graft function in six of the seven patients with this multimodal treatment. In general, until now we have had no data indicating that patients treated prophylactically with ATG induction experienced less ABMR or donor-specific antibodies.
ATG can act on B cells and plasma cells through direct or indirect pathways. Most studies evaluating ATG in the treatment strategy of ABMR are particularly reported in mixed rejection
Side effects
1 ATG is associated with higher risk of opportunistic infections and cancerespecially post-transplant lymphoproliferative disease .
2 negative impact of ATG-induced serum sickness disease (SSD) on allograft survival has reopened the debate on the intrinsic toxicity of this powerful immunosuppressant
3 ATG infusion may cause a cytokine release but less than OKT3.,
4 there were fever, chills and malaise following antibody administration.
Before administration CBC must be done to ensure no infection, ↓platelets or ↓WCC
• patient must be euvolemic not overloaded
, dialysis for patients with AR pulmonary oedema.
one hour before the dose of Thymoglobulin give:
• IV hydrocortisone 100mg
• IV H antagonist.
• PO paracetamol 1000mg
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be 6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
OKT3
is monoclonal antibody against CD3 . it’s administration leads to depletion of T cells it use has stopped .
It blocks the function of T cells and blocks the function of a molecule called CD3 in the membrane of T cell.
indicated for the treatment of acute allograft rejection in renal transplant patients.
Side effects
first doses of muromonab CD3 may be associated with cytokine-release syndrome as it activate T cells to release cytokines like tumor necrosis factor and interferon gamma.
This cytokine release syndrome, appears as skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea and could lead to life-threatening conditions like : apnoea, cardiac arrest, and flash pulmonary edema
Also it causes leucopenia, increased risk for severe infections and malignancies.
Reference
1 Couvrat-Desvergnes G , Salama A , Le Berre L et al. Rabbit antithymocyte globulin-induced serum sickness disease and human kidney graft survival. J Clin Invest 2015; 125: 4655–4665.
2 Jamal Bamoulid, Oliver Staeck, Thomas Crépinet al .Anti-thymocyte globulins in kidney
transplantation: focus on current indications and long-term immunological side effects
.Nephrology Dialysis Transplantation, Volume 32, Issue 10, October 2017, Pages 1601–1608,
____Mechanism of action____
●OKT3 was the first monoclonal antibody used to treat patients.
OKT3 acts by blocking the function of T cells which play a major role in acute graft rejection.
OKT3 reacts with and blocks the function of a molecule called CD3 in the membrane of T cell.
OKT3 is a
—->murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells blocks T cell function.
A rapid decrease in T lymphocytes occurs within a few minutes after administration of muromonab CD3.
This antibody is used mainly for the treatment of acute organ transplant rejection.
●Antithymocyte globulin (rabbit) is a polyclonal antibody which appears to cause immunosuppression by acting on T-cell surface antigens and depleting CD4 lymphocytes
________ INDICATIONS________
1- OKT3
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. Orthoclone OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients.
●ATG INDICATIONS
1-Renal transplant (acute rejection treatment): IV: 1.5 mg/kg/day for 7 to 14 days
2-Renal transplant (induction therapy): IV: 1.5 mg/kg/day for 4 to 7 days; the first dose should be administered prior to reperfusion of the donor kidney.
_________SIDE EFFECTS_______
OKT3
The first doses of muromonab CD3 are associated with a flu-like “cytokine-release syndrome includes
binding of muromonab-CD3 to CD3 that can activate T cells to release cytokines like tumor necrosis factor and interferon gamma.
This cytokine release syndrome, or CRS, includes side effects like skin reactions, fatigue, fever, chills, myalgia, headaches, nausea and diarrhea and could lead to life-threatening conditions like : apnoea, cardiac arrest, and flash pulmonary edema.
To minimize the risk of CRS and to offset some of the minor side effects patient experience, glucocorticoids (such as methylprednisolone),
acetaminophen, and diphenhydramine are given before the infusion.
Other adverse effects include leucopenia, as well as an increased risk for severe infections and malignancies typical of immunosuppressive therapies.
Neurological side effects like aseptic meningitis and encephalopathy have been observed. Possibly, they are also caused by the T cell activation.
Repeated application can result in tachyphylaxis (reduced effectiveness) due to the formation of anti mouse antibodies in the patient which accelerates elimination of the drug.
It can also lead to an anaphylactic reaction against the mouse protein which may be difficult to distinguish from a CRS.
●ATG
☆Endocrine & metabolic: Hyperkalemia (17% to 57%), hyperlipidemia (15%), hypokalemia (6% to 12%)
☆Gastrointestinal: Abdominal pain (8% to 38%), constipation (15% to 33%), diarrhea (6% to 20%), nausea (29% to 37%), vomiting (12% to 20%)
☆Genitourinary: Urinary tract infection (39% to 42%)
☆Hematologic & oncologic: Anemia (12% to 25%), leukocytosis (13%), leukopenia (21% to 63%), thrombocytopenia (9% to 37%)
☆Infection: Cytomegalovirus disease (6% to 13%), infection (17% to 76%; severe infection: 23%), sepsis (6% to 12%)
☆Nervous system: Anxiety (7% to 14%), chills (9% to 57%), headache (18% to 40%), insomnia (12% to 20%), malaise (9% to 13%), pain (26%)
☆Neuromuscular & skeletal: Arthralgia (15%), asthenia (13%), back pain (12%), myalgia (11% to 20%)
☆Respiratory: Dyspnea (15% to 28%), lower respiratory tract infection (≤13%), pulmonary disease (12%), upper respiratory tract infection (11%)
☆Miscellaneous: Fever (13% to 46%).
________M.O. ADMIN._________
OKT3 :
IV
ATG RABBIT:
IV
*OKT3
OKT3 (Orthoclone-OKT3 or Muromonab-CD3 ) is a murine monoclonal antibody specific for the CD3 antigen expressed on all human T cells.
effective as both induction therapy and in the treatment of acute rejection, but because of Of it’s serious side effects so that OKT3 is usually reserved for the treatment of severe or resistant rejection.
*Mechanism of action
• CD3 is a multimeric component of the T-cell receptor.
• Rapid (within 1 hour) activation of all CD3 cells. and cytokine release
• Clearance of >90% CD3 cells from the circulation within 24 hours
• Repeated administration is required to maintain CD3 depletion, with fully functional CD3 lymphocytes reappearing within a few days of the end of treatment
. (This is in contrast to polyclonal anti-lymphocyte Ab and alemtuzumab, both of which cause T-cell depletion persisting for months after the end of treatment).
Administration of OKT3 Precautions
Cytokine release is an unavoidable consequence of the first few doses of OKT3. Serious side effects may be minimized as follows:
• Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
• Ensure that the patient is not fluid overloaded.
Diuretics are often ineffective in the presence of AR, so use dialysis with ultrafiltration to achieve Weight within 1–2kg of dry weight
• No pulmonary oedema on CXR, and minimal peripheral oedema
• Normal BP.
• Pre-medication is essential. 30–60 minutes before the first 2 doses of OKT3 give
• IV methylprednisolone (250mg if 60kg)
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg.
• For subsequent doses, IV methylprednisolone may be replaced with maintenance oral prednisolone and the antihistamine omitted.
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
*Adverse effects
• Anaphylaxis. More common with re-exposure to OKT3.
• Cytokine release syndrome (CRS) is inevitable despite the precautions described. Almost all patients experience some symptoms 30–120 minutes after the first few doses of OKT3:
• High fever, chills and rigors in ≈90%
• ↑HR, and either ↑ or ↓ BP (30%)
• Diarrhoea and vomiting (>30%)
..Dyspnoea and bronchospasm in 10–20%, with severe non-cardiogenic pulmonary oedema in ≈2%
• Headache (30%) and aseptic meningitis. Very rarely encephalopathy, seizures and ↑ intracranial pressure (ICP) leading to brainstem herniation and death.
• ↑ infections ( especially CMV), which may be difficult to distinguish from the CRS
. • ↑ in post-transplant lymphoproliferative disorder (PTLD) by 2–3 fold in some (not all) case series.
*Polyclonal T-cell depleting antibodies
Polyclonal T-cell depleting antibodies are produced by immunizing animals with human thymic lymphocytes. The final product is purified such that it is >90% immunoglobulin, often called anti-thymocyte globulin or ATG. Several different preparations are available, and of these Thymoglobulin (rabbit ATG, or rATG) is the most frequently used. It is given as induction therapy and in treatment of acute rejection
Mechanism of action
• ATG includes antibodies against components of the T-cell receptor (CD3, CD4 and CD8), HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules.
• ATG administration has multiple effects including T-cell activation ( leading to cytokine release), clearance of T cells from the circulation, inhibition of both costimulatory and proliferative signals, and inhibition of cell adhesion and migration.
• T-cell depletion following ATG may persist for months or years (contrast with OKT3)
• ATG may have some activity to suppress B-cell and plasma cell function.
Administration of Thymoglobulin Precautions
Cytokine release leading to fever and rigors is common after the first one or two doses of any ATG preparation. Serious side effects are much less frequent than with OKT3.
• Do not give Thymoglobulin if there is untreated infection, ↓platelets or ↓WCC
• For the first dose, ensure that the patient is not fluid overloaded
.When treating AR, dialysis with ultrafiltration is required if there is pulmonary oedema.
• Pre-medication. 60 minutes before each dose of Thymoglobulin give:
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Test dose
• In some units a test dose of Thymoglobulin (5mg in 100ml 0.9% NaCl over 30 minutes into a peripheral vein) is given without pre-medication. • The aim is to exclude anaphylaxis to rabbit proteins (very unusual), which should be distinguished from the inevitable fever, chills and rigors that the test dose will precipitate.
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be 6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Adverse effects of ATG preparations
• Anaphylaxis • Cytokine release—less severe than OKT3
and largely restricted to the first dose
• ↓ WBC and platelets • ↑ infections ( especially CMV
) • ↑ in PTLD by ≈2-fold in most studies and case series
Serum sickness
• Thymoglobulin is composed of rabbit proteins, and up to 68% of patients develop antirabbit antibodies
• Very occasionally serum sickness (fever, vasculitic rash, arthralgia, and myalgia) develops as a result of immune complex formation with anti-rabbit antibodies
• Typically 5–15 days after the onset of Thymoglobulin therapy
• Self-limiting • Precludes further treatment with Thymoglobulin
• The presence of anti-rabbit antibodies alone does not preclude re-treatment with Thymoglobulin, but may reduce efficacy
. Monitoring of CD3 T cell may be required in patients receiving repeated courses.
Reference
Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011
OKT3 is monoclonal antibody against CD3 . it’s administration leads to depletion of T cells .
ATG is a polyclonal antibodies produced by rabbit or equine source after injection with human lymphocytes. It’s administration lead to :
Indications : OKT3 was used for treatment of steroid resistant acute cellular rejection .
some centers used it for induction of immunosuppression.
ATG : used for
Side effects : OKT3 : cytokine release syndrome is a major concern with OKT3 use and premedication with steroids and antihistamine should be given with monitoring of the patient . Due to this side effect and the availability of ATG , production of OKT3 had been stopped. Some patients develop antibodies against OKT3 decreasing it’s efficacy. Also fever, diarrhea , rash can occur .
ATG: Cytokine release syndrome can also occur with ATG but with lesser frequency. fever , rash , itching can occur. The most important concern with the use of ATG is the risk of infection and malignancy on the long term.
Since OKT3 production had been stopped sure I will give ATG , but even if OKT3 is available , I will give ATG because of lower toxicity and proved efficacy.
Reference:
(1) Jamal Bamoulid, Oliver Staeck , Thomas Cre´pin, Fabian Halleck
, Philippe Saas, Susanne Brakemeier , Didier Ducloux and Klemens
Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects Nephrol Dial Transplant (2017) 32: 1601–1608
doi: 10.1093/ndt/gfw368 Advance Access publication 25 October 2016
Dear All, do you think there is a role for ATG in acute antibody-mediated rejection? Please share your thoughts
no role except if it is mixed with cellular rejection
Thanks, Riham
There is a role for ATG in the treatment of AMR. See the answers below
In our practice we are commencing ATG in management of ABMR beside PLEX, pulse steroids and Rituximab.
There is some retrospective studies addressed the use of ATG in the treatment of ABMR
Rabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR).rATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.
https://doi.org/10.1016/j.transproceed.2019.02.051
Yes ATG shows diverse effects on immune system. In addition to T cell depletion it’s also induced apoptosis in B cells lineages that interferes with dentritics cells functions and lead to expression of both T -reg cells with natural killers cells
Some clinical studies suggest that ATG reduce the AMR in patients with DSA by removing the T cells that help for B cells activation by its antibodies binding to the Many of B cells proteins and induce B cell apoptosis
ATG preferred for treatment of vascular steroid resistant ACR and ABMR
Reference
Thyroglobulin and it’s use in Renal transplantion:A review
Umasankar Mathuram Thiyagaran Amirthavarshini ponnuswamyb Atul Bagulc
And Nephrol 2013;37:586-601
Well done
Role of rATG in treatment of acute rejection
Treatment of acute TCMR
• Meta-analysis that has been published 2006 studied role of monoclonal and polyclonal antibody therapy in treatment of acute rejection in kidney transplantation recipient
o Monoclonal and polyclonal antibody therapy were better than steroids in halting ongoing rejection and preventing graft loss or death with a functioning graft, but no differences in preventing subsequent rejection or death in 1 year
• KDIGO guidelines recommend corticosteroids for initial treatment of ACMR and add in maintenance prednisolone in those who are not on steroids and have rejection
Treatment of acute ABMR
• Most studies that evaluated treatment strategy of ABME had mixed rejection forms.
• One study which is retrospective analysis showed treatment of rATG based protocol (mean dose 0.79mg/kg/day) in high immunological risk had improvement in graft function and able to decrease the creatinine
• No data till now suggest rATG based induction had lesser ABMR, in fact reported 44%of those who had ATG in additional to other treatment had ABMR
• ATG is not recommended as first line treatment for ABMR
• ATG can be considered in TCMR associated ABMR
Bamoulid, J., Staeck, O., Crépin, T., Halleck, F., Saas, P., Brakemeier, S., Ducloux, D. and Budde, K., 2016. Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects. Nephrology Dialysis Transplantation, p.gfw368.
Thanks, Theepa
I agree, ATG should not be used (surprisingly it has been used) as the first line of treatment of AMR, but does it have a role?
Yes, the use of ATG in the treatment of active ABMR leads to significant reduction in serum creatinine level and proteinuria and the level of peripheral lymphocytes decreased rapidly and remained so for around 12 months.
Reference:
Nanmoku K., Shinzato T., Kubo T., Shimizu T., et al. Effect of Rabbit Antithymocyte Globulin on Acute and Chronic Active Antibody-Mediated Rejection After Kidney Transplantation. Transplantation Proceedings. October 2019,Vol 51,issue 8; 2602-2605.
ATG has a role in targeting the long lived plasma cells( the leading cause of ABMR) that are insensitive to the traditional B cells depleting agents.
Reference:
Su H., Zhang C.Y., Lin J., Hammes H.P. et al. The Role of Long-Lived Plasma Cells in Antibody-Mediated Rejection of Kidney Transplantation: An Update. Kidney Dis 2019;5:211–219.
Yes it has a role because it has effect in suppression of B lymphocytes and plasma cells
ATG has a significant depleting effect on B-cells,but their effect on DSA is not ideal .
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?ATG is given in cases of suspected or biopsy proven acute cellular rejection if serum creatinine does not decrease by day 4 of steroid treatment.
In your practice (in your opinion if you are not practising) what are the indications of ATG induction? Which one you prefer to give?We give ATG as induction to patients who are sensitized (high immunological risk).
I prefer to give ATG because our country has much experience in its use than OKT3
Is it only given for prevention of rejection as induction therapy!? What are the other indications?
Mechanism of action of OKT3
It is a murine Ig G monoclonal antibody that block CD3 .CD3 is a molecule, only in mature T cells & medullary thymocytes, near TCR which is needed for t cell activation .1
Mechanism of action of Thymoglobulin : rabbit derived polyclonal antithymocyte globulins (ATG) which results in the following
(1) T-cell depletion in blood (complement dependent ) and peripheral lymphoid tissues(phagocytosis by macrophages) and depletion of activatedT-cell(through either antibody-dependent cell-mediated cytotoxicity or Fas-dependent apoptosis
(2) modulation of cell surface molecules that provoke leukocyte/endothelium interactions
(3) B-cell apoptosis
(4) interfering with maturation and migration of dendritic cell
(5) over expression of regulatory T and NK- T cells. 2
Indication of OKT3 , doses and duration of treatment:
Induction and for treatment of initial and steroid-resistant rejections1
Dose is 5 mg per day in a single intravenous injection in less than one minute (not infusion) for 10 to 14 days .5
Indication of ATG , doses and duration of treatment:1- induction: 1.5 mg/kg once daily for 5–14 days or 3 mg/kg once daily on day 1 then 1.5 mg/kg once daily on days 2 and 3
2-Treatment of acute rejection : IV Infusion 1.5 mg/kg once daily for 7–14 days. 5
Mode Of Administration
ATG : IV infusion through an inline 0.22-μm filter into a high-flow vein(to avoid thrombophlebitis and DVT). Allow vial to reach room T° . To the 25 mg of the drug add 5 mL of sterile water ( 5 mg/mL) and Dilute in 50 ml of 0.9% sodium chloride or 5% dextrose injection. Recommended final concentration is 0.5 mg/mL. Administer initial dose over ≥6 hours and subsequent doses over ≥4 hours.
Side Effect Of OKT3:Acutely,within hours , cytokines release syndrome(fever,rigors, headache GIT side effects, dyspnoea , pulmonary edema3,Seizure,aseptic meningitis &renal insufficiency4
Side Effect Of ATG:Milder cytokines release syndrome ,thrombocytopenia,leukopenia3
Fever ,Headache ,Abdominal pain& Diarrhea
1-Norman DJ. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20. doi: 10.1097/00007691-199512000-00012. PMID: 8588230.
2- Mohty, M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 21, 1387–1394 (2007). https://doi.org/10.1038/sj.leu.2404683
3- Ernesto A. Pretto، Gianni Biancofiore، Claus Niemann، John R. Klinck، Peter D ,Oxford Textbook of Transplant Anaesthesia and Critical Care 4. Suman Kapur، Maristela Portela ,Immunosuppression: Role in Health and Diseases5-www.drugs.com
Hilda, good answer, you have answered the question ” what are the indications of ATG induction? Which one you prefer to give” in your answer with realising. Less Cytokine release with ATG and better results.
OKT 3
-OKT3is a mouse monoclonal antibody targeted at the CD3 receptor which is a membrane protein on the surface of T cells.
-It was used to treat acute several allograft rejections but know withdrawn due to its severe side effects.
-It is given as a5mg IV bolus dose administered peripherally but doesn’t give IM.
-It is used for 10 days.
-Methylprednisolone 1mg/kg given before the first dose and IV hydrocortisone given 30 min after administration to decrease the incidence of reaction to the first dose
-A low protein-binding 0.22-micron filter is used before administration of each dose
-Patient temperature should not exceed 37.8 C at the time of administration.
Side effects:
1-Anaphylaxis.
2-Cytokine release syndrome within 1st48Hr (Fever, rigors, pruritis, erythema, dyspnea, tachycardia, hypo/hypertension)
3-Very serious side effects: non-cardiogenic pulmonary edema, aseptic meningitis, and encephalopathy.
-It should not administer to volume overload patients.
-It is monitored by CD3 count.
Thymoglobulin
– It is purified polyclonal immunoglobulin. Among polyclonal antibodies are antibodies specific for components of TCR (CD3, CD4, CD8) and cytokine receptors as well as adhesion molecules.
-It acts as a rapid T-cell-depleting agent in both the blood and peripheral lymphoid tissues. The major pathways for T –cell depletion are complement-dependent cell lysis in the blood compartment and apoptotic cell death in the lymphoid tissues.
-It is used as induction therapy and treatment of acute rejection inpatient receiving a kidney transplant.
– Dose is 1.5mg/kg up to 25mg in 500ml normal saline or5% glucose.
-It should be given via a central line and a 0.22-micron in-line filter is recommended.
-Administer the first dose at 10ml/h for the first hour and subsequant infusion should be administered over ≥6h.
-Treatment should not exceed 14 days.
-Premedication: chlorphenamine 10 mg IV and hydrocortisone 100mg IV 1h before each infusion.
-It is monitored by CD3 count.
Side effects :
1-Anaphylaxis
2-Cytokine release syndrome(Fever, rigors, pruritis, erythema, dyspnea, tachycardia, hypo/hypertension)
3-Serum sickness: after 7 days of treatment. Clinical features are fever, rash, arthralgia, myalgia. It requires treatment cessation.
4-low WCC and platelet.
5-Increase the risk of infection.
6-Increase the risk of post-transplant lymphoproliferative disorder.
7-I preferred ATG because OKT3 was withdrawn due to its severe side effects.
References
1.Sgro, C. (1995-12-20). “Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review”. Toxicology. Immunotoxicology Papers presented at the Third Summer School in Immunotoxicology. 105 (1): 23–29
2.Simon steddon,Neil Ashman. Handbook of Nephrology and Hypertension. second addition
Nice answer
Muromonab CD3 (OKT3), a murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells, blocks T cell function. A rapid decrease in T-lymphocytes occurs within a few minutes after administration of muromonab CD3. It initially activates T cells, which leads to a cytokine release syndrome symptoms.
Subsequently, it both prevents T cell activation and depletes T cells. In 1986, it became the first mAb antibody approved by the FDA. It had indications for renal, cardiac, and hepatic allograft rejection. Its use was associated with a risk of infections, including bacterial, viral, and opportunistic. For this reason and the availability of alternative therapies, muromonab-CD3 was withdrawn from the market in 2010.
Antithymocyte globulin (ATG) is a polyclonal immune globulin is prepared by injecting human thymocytes into rabbits (rATG-Thymoglobulin) or horses (Atgam). Given the superior efficacy of rATG-Thymoglobulin in the treatment of acute rejection, Atgam is no longer used routinely in most transplant centers.
-Mechanism of action of Antithymocyte globulin (ATG):
ATG contains cytotoxic antibodies directed against a variety of T-cell markers induces T lymphocyte depletion in the peripheral blood basically by complement-dependent cell lysis, inhibiting B cell proliferation and inducing B cell apoptosis. After use of Thymoglobulin, a prolonged lymphopenia can persist, and the CD4 subset may be suppressed for several years.
-Indications of Antithymocyte globulin (ATG):
1-Used as Induction therapy as T Cell depleting agent in combination with lower doses of conventional agents in patients with high risk for rejection.
Thymoglobulin (rATG) (1 to 2 mg/kg) are administered intraoperatively. The initial intraoperative dose of rATG is followed by 2 mg/kg of rATG per day for the next two days (a total of three doses of cumulative doses of 6 mg/kg) rATG is administered if the white blood cell count is greater than 2000/microL and the platelet count is greater than 75,000/microL. It is mixed in 500 mL of dextrose or saline and infused over 4 to 8 hours into a central vein.
To avoid allergic reactions, the patient should receive intravenous premedication consisting of methylprednisolone, 30 mg, and diphenhydramine hydrochloride 50 mg given 30 minutes before injection. Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control.
2-Used as anti-rejection therapy: The reversal rate for acute rejection has been between 75 and 100 percent in different series.
In biopsy proved T cell mediated rejection, Banff grade IB rejection and few or no chronic histologic lesions who present less than one-year posttransplant , in patients with Banff grade II or III rejection and in expected mixed rejection.
Commence daily rATG-Thymoglobulin at 1.5 to 3 mg/kg per dose for a total dose of 5 to 10 mg/kg. The total number of doses is determined by severity of Banff grading.
CMV and PCP prophylaxis must be given during treatment with rATG-Thymoglobulin.
A decrease in serum creatinine to within 10 percent of the baseline level is considered to be successful reversal of rejection.
Great, do you have any evidence based studies to supplement your answer
Sure,
1-Kirk AD. Induction immunosuppression. Transplantation 2006; 82:593.
2-Wiland AM, Fink JC, Weir MR, et al. Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial. Transplantation 2004; 77:422
Thymoglobulin is the preferred drug.
Muromonab-CD3 (Orthoclone OKT3) is the first monoclonal antibody used in clinical medicine and was introduced in 1985.
Largely because of frequent, life threatening first dose reaction, it is no longer used and in transplant is replaced by thymoglobulin.
Thymoglobulin
Mechanisms of action:
Thymoglobulin is a polyclonal antibody preparation. It contains cytotoxic antibodies directed against a variety of T cell markers. Its mechanism is depletion of peripheral blood lymphocyte, in particular T cells are either lysed or cleared by the reticuloendothelial system and their surface antigens may be covered by the antibody.
· T cell depletion constitute the primary mechanism.
· other mechanisms, such as modulation of cell surface antigens
· Induces lymphocyte depletion in the peripheral blood by complement-dependent cell lysis.
· Significant percentage of lymphocyte depletion can be antibody-mediated cytotoxicity and activation-induced cell death.
· Depletes T cells not only in the periphery but also in secondary lymphoid tissues where the vast majority of T cells reside and antigen presentation occurs (notably not in the thymus)
· Down-modulates the expression of several molecules that control T-cell activation, including the T-cell receptor (TCR)/CD3 complex, CD2, CD4, CD5, CD6, and CD8
· Down-regulate the cell surface expression of a number of integrins and intercellular adhesion molecules (ICAMs) that facilitate leukocyte adhesion to the endothelium
· Strongly induce apoptosis in vitro against naive, activated B cells
· Bind with numerous B-cell surface proteins and it is this cross-linking of CD30, CD38, CD95, CD80, and HLA-DR that likely accounts for this activity.
Advantages:
· May reduce the risk of AMR in patients with preformed donor-specific antibody presumably by removing T-cell help for alloreactive B cells and via B-cell depletion due to antibodies which directly bind B cells
· Interference with dendritic cell functional properties, and leads to induction of regulatory T and natural killer T cells. Thymoglobulin causes sustained and rapid expansion of CD4+CD25+FOXP3+regulatory T cells that play an important role in immune modulation and limiting alloimmunity.
· Thymoglobulin blocks multiple antigens related to IRI, in addition to its better-known T cell depleting effects.
· Treatment with thymoglobulin accompanies by lower incidence of DGF.
· Lower incidence and severity of acute rejection as well as chronic rejection with treatment with thymoglobulin.
· Improvement in graft and patient survival rate
The complex and prolonged immunomodulation induced by ATG contributes to the efficacy of this agent.
Lymphocyte depletion occurs rapidly after intravenous administration and recovery of T cell counts occurs gradually. For example, in one study, about 40% of patients treated with thymoglobulin recovered more than 50% of initial lymphocyte count in 3 months.
Following administration of thymoglobulin, a prolonged lymphopenia may ensue and the CD4 population can be suppressed for several years that may account for lower frequency of rejection episodes.
The standard dose of thymoglobulin is 1.5 mg/kg in a course lasting 4-10 days. Although doses above 6 mg/kg are probably not necessary for kidney transplantation. The route of administration is intravenous infusion into a central vein or arteriovenous fistula after mixing in dextrose or saline IV fluid over 4-8 hours. Administration should be started intraoperatively because there is significantly lower incidence of DGF. Premedication with methylprednisolone, diphenhydramine, and acetaminophen for prevention of allergic reaction and monitoring of vital signs are advised.
Adverse effects:
· Thymoglobulin can cause acute and delayed reactions. Acute reaction will present as cytokine release syndrome which is characterized by anaphylaxis, fever, chills/rigors, dyspnea, nausea/vomiting, diarrhea, hypotension or hypertension, malaise, rash, and/or headache which usually can be managed by stopping infusion and epinephrine.
· Severe reaction includes cardiorespiratory dysfunction including hypotension, pulmonary edema, myocardial infarction, tachycardia and rarely death.
· Delayed reactions usually present as serum sickness. Serum sickness tends to occur 5–15 days after the onset of thymoglobulin therapy which presents as fever, rash, arthralgia, and/or myalgia, and is treated with corticosteroids.
· Thymoglobulin is not specific for T cells but contains antibodies directed against different blood cell types (T cells > B cells; NK cells > monocytes; neutrophils > platelets > erythrocytes)
· Because of the presence of cross-reacting antibodies against non-lymphoid cells, hemolytic anemia, thrombosis, thrombocytopenia and neutropenia can occur.
· Leukopenia and thrombocytopenia can necessitate reduction or curtailment of drug dosage.
· Infection, most commonly with CMV, may be a late adverse sequela that is related to overall amount of immunosuppression. Other infections include sepsis, candidiasis, herpes simplex, and UTI.
· Development of lymphoproliferative disorder (fulminant B cell lymphoma) is increased with treatment with thymoglobulin in transplant recipients.
Despite these adverse effects, thymoglobulin has been shown to be safe in renal transplant recipients when administered in a planned and monitored setting.
Mehrabi A, Mood ZhA, Sadeghi M, Schmied BM, Müller SA, Welsch T. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant. 2007 Sep;22
Umasankar Mathuram Thiyagarajan, Amirthavarshini Ponnuswamy, Atul Bagul. Thymoglobulin and Its Use in Renal Transplantation: A Review. Am J Nephrol 2013;37:586–601
God answer
OKT3 is a monoclonal antibody targets CD3 antigen receptor of T-lymphocytes. while thymoglobulin is a poly antibodies against T-cell receptor (CD3 , CD4 and CD8) , HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules. thymoglobulin may have some activity against B-cell .
Administration of OKT3 can be associated with serious side effects due to rapid rebound of functional CD3 . while serious side effects are less frequent with thymoglobulin use .
Efficacy
OKT3 reverses >90% of first and 66% of steroid-resistant AR episodes. The presence of anti-rabbit antibodies alone does not preclude re-treatment with Thymoglobulin, but may reduce efficacy. Monitoring of CD3 T cell may be required in patients receiving repeated courses.
Adverse effects
Anaphylaxis is more common with re-exposure to OKT3.
Cytokine release syndrome (CRS) is inevitable despite the precautions . Almost all patients experience some symptoms 30–120 minutes after the first few doses of OKT3 . while in thymoglobulin cytokine release—less severe than OKT3 and largely restricted to the first dose. CRS can be seen in form of fever , headache ,vomiting ,diarrhea ,dyspnoea ,tachycardia and hypotension .
Risk of infection is increased in both.
↑ in post-transplant lymphoproliferative disorder (PTLD) is also increased in both.
Very occasionally serum sickness (fever, vasculitic rash, arthralgia, and myalgia) develops as a result of immune complex formation with anti-rabbit antibodies (thymoglobulin) .
Precautions
Serious side effects may be minimized as follows:
Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
Ensure that the patient is not fluid overloaded.
No pulmonary oedema on CXR, and minimal peripheral oedema.
Normal BP. Test dose
Weight within 1–2kg of dry weight .
Pre-medication
is essential. 30–60 minutes before the first 2 doses of OKT3 and before each dose of thymoglobulin.
• IV methylprednisolone (250mg if <60kg, 500mg if >60kg) ,hydrocortisone 100 mg is enough in thymoglobulin .
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg.
•Ensure prophylaxis against PCP, CMV and oral candidiasis
Dose
• OKT3 is given as an IV bolus of 5mg (2.5mg for children <30kg) into a peripheral vein. Give daily for 10 days .
In thymoglobulin;
•Induction therapy—6mg/kg, with the first dose of 1.5mg/kg administered intra operatively, and subsequent doses daily, or on postoperative days 1, 3 and 5.
•Rejection therapy—typically 1.5mg/kg daily for 10–14 days, with daily dose determined by monitoring of FBC ± CD3 cell count .
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be <0.5mg/ml).
• Thymoglobulin must be given into a central vein
• Following pre-medication, Thymoglobulin is given as an IV infusion over >6 hours (first dose) or >4 hours (subsequent doses).
• ↓ the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Maintenance IS
There is a very variable approach to the administration of maintenance IS during Thymoglobulin therapy.
Monitoring
•Unlike other depleting antibodies, OKT3 rarely causes thrombocytopaenia or leukopaenia.
•Efficacy can be monitored by daily flow cytometry to identify CD3 cells. If CD3 cells >0.05×10 /L then ↑ dose to 10mg daily (usually only required for repeated courses of OKT3).
Thymoglobulin monitering
Measure FBC daily
• If platelets <75×10 /L → half dose, <50×10 /L → omit
• If WCC <3.0×10 /L → half dose, <2.0×10 /L → omit.
Reference;
Chang PC-W, Hricik DE. What are immunosuppressive medications? How do they work? What are their side effects? In McKay DB, Steinberg SM (eds).
Kidney Transplantation: A Guide to the Care of Kidney Transplant Recipients, New York, Springer, 2010; pp 119–135.
Danovitz GM. Immunosuppressive medications and protocols for kidney transplantation. In Danovitch GM (ed).
Handbook of Kidney Transplantation, 5th ed, Philadelphia, Lippincott Williams & Wilkins, 2010, pp 77–126.
Kidney Transplantation- Principles and Practice. Morris PJ, Knechtle SJ (eds). Philadelphia, Elsevier Saunders, 7th ed, 2013
.
Dear All
indication of atg induction?
high immunlogical risk patient like
a-cadaveric kidney transplant
b-more than 3 mismatches espically class 2 mismatches in living donation
c-prevoius transplantion
d-prescence of dsa befor transplantion
e-abo incompatible transplantion
f-postivel luuminx and negative flow cytometry crossmatch
dosage 4-6 mg kg, cumaulative dose can be given in 4 divide dose or more according to pt cbc(wbc, plt) monitoring on daily basis .
indication of atg in acute rejection?
based on histopathology and pt history of dsa befor transplantion .
banff criteria is used to deterimine the sevirty of rejection and clasissifcation of wether it is TCMR OR AMR or non immunological causes.
in AMR atg is indicated wether prescnce of c4d or not , may be accomapnied with iv igg or palsmapharesis.
IN TCMR WE USED IN OUR CENTRE TO GIVE ATG WHEN BANF GRADE 2A OR ABOVE WITH APPERANCE OF INTIMAL ARTERITIS .
reffernce
Kidney Res Clin Pract Published online March 13, 2020 pISSN: 2211-9132 • eISSN: 2211-9140 https://doi.org/10.23876/j.krcp.20.003
Thanks, Mohamed
I disagree with this” more than 3 mismatches especially class 2 mismatches in living donation”. What is the reference?
Also, noticed many typos in your answer, but I admire you for your hard work and your reflection.
Thanks prof , TYpos i will try to avoid it. Regarding my reffernce is kidgo guidlines 2009 for transplant recipent. American Journal of Transplantation 2009; 9 (Suppl 3): S6–S9
Indication for ATG induction therapy :
————————————————–
high immunological risk.
DD – kidney transplant.
more than 3HLA mis-match in LDT
Pediatric age group.
previous senesitization , previous kidney transplantaion , pre-transplant DSA postivewith PRA >20%
ABO incompatable transplantaion
ATG doses for induction 1.5mg/Kg given 3-4 doses , frist dose intraopertaive or post operative ( based on centre experinece ) and first 3 doses will be given daily with close monitring with FBC , lymphcytes % , total cummulative dose prefered in LD transplant not more than 6mg/ kg , RANGE 4-6mg/kg .
Indication of ATG in acute rejection
————————————————–
Steriod resistant ACR
ABMR with vascular injury as intimal arteritis sometimes diffiult to differentite by histology with the other limitation like in commertial transplantaion we cant perform DSA , so in suspected cases of vascular involvemnt with intimal artirtits will go ahead with ATG to cover for possible mixed type of rejections.
dosing same 1.5mg /kg for 3-4 doses depend on response and toleration of the therapy, total cummulative doses of ATG for induction and rejection treatment should not be more than 9mg/kg in order to aviod serious side effects including the apportunesitic infections like CMV, PJP and malignancies .
prefered to give CMV prophylaxis in the first 6 weeks of the course with transient reduction of MMF dosing .
Adding to the list of high risk and prefere induction with ATG :
————————————————————————————
younger recipient and old donor.
DGF .
Long cold ischemia time> than 24h .
black race
some centres including ours we use ATG even in LD with low immunologic risk with dose modifications less frequency and lower cummulative doses 1-1.5mg/kg of 3-4 doses maximum ,as we have only ATG as induction IS we have limited access to monoclonal AB like basiliximab or donzamab.
-UpTODATE,, kidney transplantation in adult: induction immunosuppressive therapy , 2021.
Thanks, Saja
I disagree with this” more than 3 mismatches especially class 2 mismatches in living donation”. What is the reference?
indications of ATG induction:
1- high immunological risk patient like DSA pretransplant , PLNF(positive luminex negative flow cytometry), 2nd or more transplant.
2- deceased donor
3- female recipient with male donor.
4- African recipient.
dose 1.5 mg/kg/dose for 3-7 days , given over 4- 6 hrs iv infusion in central line , with premidication used as paracetamol injection, methylprednisolone and antihistaminic iv,
3 mg /kg is the 1st dose given intraoperative.
ATG in acute rejection :
used to treat acute cellular rejection not responding to pulse steroid therapy (resistant) which may be alone or mixed with antibody mediated rejection (which is treated originally by plasmapharesis and IVIg)
Thanks, Riham
I disagree with this” female recipient with male donor.”. What is the reference?
Induction immunosuppressive therapy in kidney transplantation depends on the recipient’s risk of acute rejection. In patients with high risk for rejection, r-ATG is given instead of anti IL2.
According to 2009 KDIGO clinical practice guidelines, risk factors for acute rejection include one or more of the following:
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African-American ethnicity (in the United States)
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
Route of administration
The first dose is given over at least 6 hours; subsequent doses may be infused over at least 4 hours. Infuse through a central line but can also be given in peripheral line. To avoid or to reduce severity of infusion related reactions, premedicate with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to infusion.
Dose
For induction therapy r-ATG is given IV at 1.5 mg/kg/day for 4 to 7 days with the first dose should be started in the way to the surgery.
For acute rejection r-ATG is given at dose of 1.5 mg/kg/day IV for 7-14 days
ATG therapy indicated in the following
●One or more human leukocyte antigen (HLA) mismatches
●Younger recipient and older donor age
●African-American ethnicity
●Panel reactive antibody (PRA) greater than 0 percent
●Presence of a donor-specific antibody (DSA)
●Blood group incompatibility
●Delayed onset of graft function
●Cold ischemia time greater than 24 hours
In such patients, the 2009 KDIGO guidelines suggest the use of lymphocyte-depleting agents, which are potent immunosuppressive agents, rather than interleukin (IL) 2 receptor antibodies.
*ATG therapy indicated in (TCR) in the following
if there is any evidence of vascular involvement (Banff 2A)
Banff 2B/3 rejection
Steroid-resistant
*ATG therapy indicated in (AMR) in the following
AMR is almost always associated with TCMR, and in any case Ab-mediated immune responses require T cell help.
Treat vascular inflammation and TCMR with :
• IV methylprednisolone for the first 3 days of treatment
• T-cell-depleting Ab (Administer after PEX/IA treatment, or on non-PEX/IA days.)
*Dosing strategies for rATG-Thymoglobulin
Our practice
●seven-day course of rATG-Thymoglobulin at 1.5 mg/kg intravenously 6–8 hours via central line intraoperatively, then daily for six days.
Reference
1-Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011
2-Up to date Oct 2021.
In your practice (in your opinion if you are not practising) what are the indications of ATG induction?and what is the dose and the duration of treatment?
ATG is used for induction in high immunological risk transplantation as:
The dose for induction is 1-1.5 mg/kg, the duration is from 4-14 days.
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?
In cell mediated rejection the indication is steroid unresponsive acute TCM rejection.
In ABMR the indication is in case of unresponsiveness to other immunosuppressive medications as this type of ABMR is thought to be caused by long lived plasma cells that are insensitive to traditional immunosuppressive that remove B cells.
Reference:
Su H., Zhang C.Y., Lin J., Hammes H.P., et al.The Role of Long-Lived Plasma Cells in Antibody-Mediated Rejection of Kidney Transplantation: An Update. Kidney Dis 2019;5:211–219.
OKT3
Mechanism of action
a monoclonal antibody directed against the CD3 antigen on peripheral T cells, It initially activates T cells, which leads to a cytokine release syndrome ,then it prevents T cell activation and depletes it ,blocking it’s function.
Indication
for the treatment and prevention of acute transplant rejection.
for the treatment of T cells acute lymphoblastic leukemia
Side effects
-flu-like “cytokine-release syndrome” symptoms, headaches, diarrhea, nausea, and vomiting.
-may lead to life threatening status ; apnea, flash pulmonary edema and cardiac arrest.
-Leucopenia and neurological side effects
-Increases risk of infections, including bacterial, viral, and opportunistic.
Mode of administration
IV administration with 100% bioavailability
References
-Eric Scholar, in xPharm: The Comprehensive Pharmacology Reference, 2007
– In Meyler’s Side Effects of Drugs (Sixteenth Edition), 2016
– Harrison S. Pollinger D.O., Paul F. Gores M.D., in Cellular Transplantation, 2007
-Robert Eisenberg, in Stiehm’s Immune Deficiencies, 2014
Thymoglobulin
Mechanism of action
-induces lymphocyte depletion by complement-dependent cell lysis which is not the only mechanism as a large percentage of lymphocyte depletion can be done by antibody-mediated cytotoxicity
-in lower conecntations it induce lysis of preactivated T cells while at higher concentration it triggers CD178 (CD95-L) expression by resting T cells and apoptosis of preactivated T cells by mostly involving Fas/Fas-L interactions
-can cause apoptosis to activated B cells and bone marrow resident plasma cells it binds with numerous B-cell surface proteins and it is the cross-linking of CD30, CD38, CD95, CD80, and HLA-DR that likely enables this activity.
-Also it interference with dendritic cell functional properties, and leads to induction of regulatory T and natural killer T cells.(#)
Indication
– for the prophylaxis and treatment of acute rejection in transplanted patients with concomitant immunosuppression
– Aplastic anemia
-Myelodysplasia
-Graft versus host disease
Side effects
Abdominal pain ,UTI ,Asthenia ,Chills ,Diarrhea ,Dyspnea , fever ,Headache
HTN , Hyperkalemia ,infection as Hepres simplex ,Leukopenia ,Nausea , Pain
Peripheral edema ,Tachycardia ,Thrombocytopenia ,Dizziness, Gastritis
Oral moniliasis
Mode of administration
IV route
recommended before admistration to give corticosteroids, acetaminophen, and/or an antihistamine 1 hr before each infusion; to reduce the infusion-associated reactions
Infuse first dose over at least 6 hr and the following doses over at least 4 hr
Stored refrigerated between 2-8°C , need to be protected from light and freezing
References
Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.
(#)Thiyagarajan UM etal. Thymoglobulin and Its Use in Renal Transplantation: A Review. Am J Nephrol 2013;37:586–601
Thanks Doaa
OKT3 is withdrawn from the market and not in use any more due to its side effect
1-WHAT IS THYMOGLOBULIN?
polyclonal antibodies made by immunization of rabbits with human lymphoid tissue . and then harvesting the resultant immune sera to obtain gammaglobulin fractions.
a- mechanism of action,
the product contain cytotoxic antibodies directed against a variety of T-cell markers. After their administration, there is depletion of peripheral blood lymphocytes. The lymphocytes, T cells in particular, are either lysed or cleared by the reticuloendothelial system, and their surface antigens may be masked by the antibody. Of particular importance.
b- dosage form
for induction immuonsuprrion and rejection eposiode like AMR 4-6 mg kg/cumulative dose didved on 4-10 days given in central line over 4-8 hours , (can be given in av fistula mixed with 1000 unit of heparin to prenent thrombosis), porceded by 1000 mg of actiamenophenand diphynhydramine to prevent allerigic reactions
c-side effects
during adminstration, fever ,chills and may cause svere anaphylactic recations and adminstrian sulod be stopped at this level, serum sickness rarely occurs becausse of pre adminstion drugs given .
after adminstrioan , lecuopeina mayoccur up to 50% and also trhromboytopenia , and next dose should be halved either a platelet count of 50,000 to 75,000 cells/mL or a white blood cell count of less than 3,000 cells/mL and if the wbc or platelt still contiue to drop on daily basis assement ,atg should be hold till recovery of both values.
also Infection, most commonly with CMV, may be a late adverse sequela of depleting antibody use.
2-WHAT IS OKT3 ?
a-MECHISM OF ACTION Orthoclone OKT3 (muromonab-CD3) was the first monoclonal antibody used in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface. OKT3 reacts with and blocks the function of a 20,000-dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following Orthoclone OKT3 administration
b-dosage form
dose 5mg to be geive through intravenous infusion (Iv) through mill pore filter as bolus dose with premedications .
Daily dose for 10 days, some they give shorter course 5 days, preferred to be given in hospital due to risk of sever life threatening side effect following first few doses due to cytokines release syndrome as the patient will have fever rigor with in first hour of the infusion and remain for 2-3 days after induction with OKT3.
i dont have any expeirnce in dealing with okt3 so i used to give rTAG for high immulogical risk pt.
reffrences
1-Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
2-handbook of kidney transplantion third edition
What is the difference between OKT3 and Thymoglobulin in terms of mechanism of action, indication, side effect and mode of administration?
Which one you prefer to give?
Whats the difference between monoclonal and polyclonal ABS:
Monoclonal antibodies (m ABs) they are homogenous AB , every AB is identical in its protein sequence so expected every antibody to have the same antigen recognition site ,affinity biologic interaction and downstream biologic effects , while the polyclonal ABs are heterogenous in protein sequence and recognize heterogenous epitopes on an antigens.
OKT3 muromonab – AB (m-ABS, IgG) :
this drug has been inuse since 1987 for both induction and treatment of acute rejection by inducingT-cell depletion effect by binding to the subunit of the CD3 complex receptors lead to subsequent deactivation and endocytosis ofCD3 complex and also deactivate the killer Tcells.
Dose and administration, side effects:
OKT3 standard dose 5mg to be geive through intravenous infusion (Iv) through mill pore filter as bolus dose with premedications .
Daily dose for 10 days, some they give shorter course 5 days, preferred to be given in hospital due to risk of sever life threatening side effect following first few doses due to cytokines release syndrome as the patient will have fever rigor with in first hour of the infusion and remain for 2-3 days after induction with OKT3 , if fever prolonged for more than 3 days should consider investigation for infection
Infection risk is high with both monoclonal and polyclonal depleting agents
Non cardiogenic pulmonary edema is one of life-threatening side effect after the first or second dose of OKT 3 especially in patient with volume overload thats why it’s important to ensure good UF prior to OKT3 administration and need close monitoring of volume status during the induction therapy.
Neurological side effects vary from mild headache to encephalopathy and aseptic meningitis.
Malignancy, increased risk of lymphoma .
Rejection rate up to 60% but usually mild with good response to steroid pulses with good maintenance IS with CNI based.
Because of wide spectrum of side effect and cost in addition with the introduction of the new different types of mABs since 1990s in the markets this drug no more consider as part of induction protocol world wide and in US its removed from the protocols ,Im not familiar with its use its not part of our transplant protocaol.
Polyclonal thymoglobulin Abs:
Rabbit ATG, thymoglobulin,prepared by immunization of rabbits with human lymphoid tissue. Atgam which is made from immunizations of horses with human lymphoid tissues.
Thymoglobulin ( Gnezyme ) in USA
ATG Fresenius in Europe (Activated human T cells).The exact mechanism of action not fully understood, its act as peripheral blood lymphocytes depleting agent, it causes sustained and rapid expansion of the CD4, CD25, Foxp3 Treg that play central part in sustained suppression of immune response and reduce the risk of rejection
CD4 can be suppressed for years following the ATG therapy.
Indication, administration:
ATG polyclonal AB used for both induction protocols and treatment of rejections, both steroid resistant ACR and ABMR , mixed type rejections .
ATG always should be given in hospital setting prefered through central line for slow IV infusion 6-8 hours with premedication’s like IV paracetamol antihistamine and IV steroid to avoid anaphylaxis allergic reaction some they preferred to be given in ICU setting.
Standard dose for induction 1-1.5mg /Kg,first dose tobe given intra- operative and then daily with close FU with FBC,WBC and the lymphocytes percentage ,vitals to be checked every 15 minutes in first hour and then hourly total dose should not exceed 6mg/kg ,and total accumulative dose for any rejection episodes should not more than 9mg/kg due to the side effect on long term including malignancy and opportunistic infections
During use of ATG preferred to hold other IS medication like MMF and reduce the dose of CNI to avoid further worsening of hematological side effects including bone marrow suppression and increased infection rate
Side effects of polyclonal ATG
1-Allergic reaction including anaphylaxis, fever rigor arthralgia and rare event of serum sickness when patient will develop fever, arthralgia, malaise, rash usually responding to steroids, allergic side effect is less compared to OKT3 mABs.
2-Hematological side effect like leucopenia thrombocytopenia ,we need close monitor and dose reduction and spacing if wbc count < 3000 ,platelet count 50-100,000 ,and even stop if WBC < 2000 and ;lymphocytes % < 0.1% .
3-Infectionincluding CMVit depends on total courses and total cumulative dose of ATG its can be late side effect that’s why some centers they start CMV prophylaxis therapy either before or during the ATG depleting course especially in recipient with +ve CMV serology.
4- Malignancy, one of the concerning side effects of ATG is the lymphoma post-transplant especially recipient with EBV negative serology and donor + including aggressive type B -cell lymphoma which is fatal and aggresive that can developed with in the first months post transplantation.
Which one you prefer to give?
I’m currnetly very familiar with ATG polyclonal AB( thymoglobulin , Gnezyme ),its part of our transplant protocol for induction using it as intra-operative infusion for first dose followed by another 2-3 doses its depends ,total doses not more than 4.5-6mg /kg for induction protocol,also we used for treatment of steroid resistant ACR,and mixed rejection ABMR/ACR .using through centrral and peripheral in e that well secures as slow iv infusion over 6-8 hours by peripheral line and 4-6 hours through central linewith premedication 30 minutes prior to the infusion ( IV paracetomal 1gm and PMP250mg ,antihiatmine 10mg iv ), we monitor with FBC and% of lymphocytes.
References:
Handbook of kidney transplantation by Gabriel M. Danovitch, FifithEdition.
Excellent answer
Orthoclone muromonab-CD3:
mechanism of action:
Lymphocyte depleting antibodies that target the CD3 complex on T cells leading to inhibition of activation and proliferation of T cells. (1)
indications:
discontinued from clinical use
was used in induction therapy (1)
was approved for treatment of acute steroid resistant rejection of solid organ transplant. (2)
Side effects:
first dose reaction due to cytokine release and may lead to capillary leak syndrome with pulmonary edema and respiratory failure (3)
treatment failure due to development of anti-OKT3 antibodies (4)
studies showed increased risk of post transplant lymphoproliferative disease with OKT3 (5)
Mode of administration:
5mg IV bolus daily for 10 days
Thymoglobulin:
mechanism of action:
Polyclonal immunoglobulin G directed against multiple T cell antigens
lymphocyte depletion through: (6)
decrease activation of T cells through downregulation of TCR/CD3 complex. (7)
Indication:
Prophylactic induction therapy to reduce the rate of early graft rejection and allow early withdrawal of steroids. (8)
decrease incidence of delayed graft function especially when started intraoperatively. (9)
KDIGO guidelines recommend using T cell depleting antibodies for induction in patients with high immunological risk (10)
KDIGO guidelines suggest using T cell depleting antibodies in treatment of recurrent acute cellular rejection that don’t respond to corticosteroids (10)
Side effects:
Cytokine release with rapid infusion
thrombocytopenia and leucopenia in 50% of patients. (9)
increase risk of postoperative opportunistic infections (CMV is the most common) (9) increase risk of malignancy especially post transplant lymphoproliferative disease. (11)
Mode of administration (9)
standard dose of rATG is 1.5 mg/Kg for 4-10 days.
administered in central vein
to avoid allergic reaction, acetaminophen, diphenhydramine hydrochloride and hydrocortisone given as premedication
vital signs are monitored during administration
The dose should be halved if platelets count 50,000-75,000 or white blood cell count <3,000 and should be stopped if count decrease more.
Therapeutic effect monitored by absolute count of lymphocytes <0.1%
(1) Norman DJ, Kahana L, Stuart FP, et al: A randomized clinical trial of induction therapy with OKT3 in kidney transplantation. Transplantation 55:44-50, 1993.
(2)Grgic, I. and Chandraker, A., 2018. Significance of biologics in renal transplantation: past, present, and future. Current opinion in organ transplantation, 23(1), pp.51-62.
(3) Padiyar, A., Augustine, J.J. and Hricik, D.E., 2009. Induction antibody therapy in kidney transplantation. American journal of kidney diseases, 54(5), pp.935-944.
(4) Chouhan KK, Zhang R. Antibody induction therapy in adult kidney transplantation: a controversy continues. World J Transplant 2012; 2:19–26
(5) Opelz G, Dohler B: Lymphomas after solid organ transplantation: A Collaborative Transplant Study report. Am J Transplant 4:222-230, 2003
(6) Mueller TF. Mechanisms of action of thymoglobulin. Transplantation 2007;
84: 5–10
(7) . Pre´ville X, Flacher M, LeMauff B et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 2001; 71: 460–468
(8) Malvezzi P, Jouve T, Rostaing L. Induction by anti-thymocyte globulins in
kidney transplantation: a review of the literature and current usage. J Nephropathol 2015; 4: 110–115
(9) Handbook of kidney transplantation by Gabriel M. Danovitch, Sixth Edition
(10) Kidney Disease: Improving Global Outcomes Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9: S1–S157
(11) Lim WH, Turner RM, Chapman JR et al. Acute rejection, T-cell-depleting antibodies, and cancer after transplantation. Transplantation 2014; 97:817–825
Thank you Heba for your answer .Just emphasizing some points:
the ceiling level for repeated cources of ATG is limited by a total cumulative dose in repeated rejection is not more than 9mg/kgm.
during ATG cource reduce or dc. the antimetamolites MMF.
Thymoglobulin:
Dosage and Administration
Induction: 1.5 mg /kg/dose (actualbody weight) (roundto the nearest 25 mg) Before each dose, the patient may be pretreated with diphenhydramine 25- 50 mg POIIV and acetaminophen 650 mg PO 1 hr prior infusion.
Thymoglobulin should be given after the scheduled methylprednisolone dose Thymoglobulin dose must be diluted in normal saline (usually 250 mL] to a
concentrationnotexceeding0.5 mg/mL.
1st dose should be infused over a minimum of 6 hrs into a central line through
an in-line 0.22 pm filter. Subsequent doses can be given over 4 hrs.
Peripheral administration: Thymoglobulin should always be given through a central line, however, peripheral administration has been used in Europe (not approved in the USA). For peripheral administration thymoglobulin should be diluted in 500 cc NS, heparin 1000 units and hydrocortisone (20-100 mg) are added to the bag.
Monitoring
Vital signs (temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation] should be monitored prior to the start of the infusion, then every 15 minutes for the first hour, then every 30 minutes for the second hour, and then hourly until the end of the infusion.
OKT3 – OKT3 (Muronab-CD3, Orthoclone)
was the first monoclonal anti lymphocyte antibody used in clinical transplantation.
It binds to the lymphocyte CD3 complex, resulting in rapid cell lysis, therefore inhibiting almost all T-cell functions.
Currently, few pediatric transplant recipients receive OKT3 for induction therapy because there is no clear benefit of OKT3 compared with other anti lymphocyte antibody preparations and it has significant adverse effects.
This includes the “first-dose reaction,” which occurs in more than two-thirds of patients, and consists of fever, chills, headache, vomiting, diarrhoea, hypotension, and occasionally pulmonary oedema. In addition, the use of OKT3 is limited by the formation of anti-OKT3 antibodies, which commonly occurs in children.
I think because of side effects and no significant benefit above ATG.OKT3 of limited use
uptodate.com
Antilymphocyte antibodies – Antilymphocyte antibodies include both polyclonal and monoclonal antibodies.
Thymoglobulin is a polyclonal immunosuppressive agent that is generated in rabbits, commonly referred to as rabbit antithymocyte globulin, or rATG. Thymoglobulin is indicated as induction therapy and as a treatment of acute rejection in patients receiving a kidney transplant. Polyclonal antibodies contain antibodies to a wide variety of human T-cell surface antigens, including the major histocompatibility complex (MHC) antigens. Another polyclonal antibody, Atgam, is a purified gamma globulin solution. It is obtained by immunization of horses with human thymocytes.
Thymoglobulins is given as slow infusion. Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to each infusion of Thymoglobulin is recommended and may reduce the incidence and intensity of infusion-associated reactions.
Serious immune-mediated reactions, including anaphylaxis or severe cytokine release syndrome (CRS), have been reported with the use of Thymoglobulin. Fatal anaphylaxis has been reported. Other adverse effects include hematologic effects, such as low counts of platelets and white blood cells (including low counts of lymphocytes and neutrophils), Infection, Malignancy, urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, headache, anxiety, chills, and increased potassium levels in the blood.
Orthoclone OKT3 (muromonab-CD3) was the first monoclonal antibody used in organ transplantation. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface. OKT3 reacts with and blocks the function of a 20,000-dalton molecule (CD3) in the membrane of human T cells that has been associated in vitro with the antigen recognition structure of T cells and is essential for signal transduction. T cell activation results in the release of numerous cytokines/lymphokines, which are felt to be responsible for many of the acute clinical manifestations seen following Orthoclone OKT3 administration.
Orthoclone OKT3 is indicated for the treatment of acute allograft rejection in renal transplant patients. Also OKT3 is indicated for the treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients.
Anaphylactic and anaphylactoid reactions may occur following administration of any dose or course of Orthoclone OKT3. In addition, serious, occasionally life-threatening, systemic, cardiovascular, and central nervous system reactions have been reported following administration of Orthoclone OKT3. These have included: pulmonary oedema, especially in patients with volume overload; shock, cardiovascular collapse, cardiac or respiratory arrest, seizures, coma, cerebral oedema, cerebral herniation, blindness, and paralysis. Pre-treatment with methylprednisolone is recommended to minimize symptoms of Cytokine Release Syndrome.
References:
1. Norman DJ, Leone MR. The role of OKT3 in clinical transplantation. Pediatric nephrology. 1991 Jan;5(1):130-6.
2. Manis JP, Feldweg AM. Overview of therapeutic monoclonal antibodies. UpToDate. Waltham, MA: UpToDate Inc.[ažurirano 08.05. 2020. Accessed on Nov 2021
3. https://www.drugs.com/pro/orthoclone-okt3.html, accessed on Nov 2021
4. https://www.drugs.com/pro/thymoglobulin.html , accessed on Nov 2021
Good use of references.
Thymoglobulin the mechanism is not fully understood but depletion of lymphocytes does occur .OKT3 blocks T cell function by direct monoclonal antibody against CD3 .Both are indicated in treatment of acute rejection .ATG also use as induction .side effect both of them cause fever, nausea ,SOB and chills . ATG cause hyperkalemia ,leucopenia and high blood pressure .OKT3 cause abnormal heart rhythm ,chest pain and dizziness . ATG 1.5mg/kg in NaCl over 6-8 hour via central line .OKT3 2hour infusion to reduce side effects .
Thanks Dalia
This is a very short answer. Please expand.
Antilymphocyte antibodies are antibodies that kill bound T lymphocytes, 2 types exists :
A- Polyclonal antibodies : antibodies produced to many hematopoietic antigens (CD2, 3, 4 ,8, 18) raised from animals (rabbit, hoarse), immunized with human lymphocytes, lymphoblast or thymocytes, 2 preparations are available :
1. Anti-thymocyte globulin (ATGAM) derived from horse
2. rATG-thymoglobulin derived from rabbit
NB: Incidence of acute rejection was found to be lower in patients receiving rATG- thymoglobulin when compared to ATGAM.
B- Monoclonal antibodies : are antibodies produced to specific TCR, include the following
1. OKT3 – OKT3 (Muronab-CD3, Orthoclone)
2. Alemtuzumab (Campath-1H) – humanized panlymphocytic (both B and T cells) anti-CD52 antibody .
rATG (thymoglobulin)
Mechanism of action :
A polyclonal antibodies to many hematopoietic antigens, raised from rabbet, immunized with human lymphocytes.
Indications :
1. Induction treatment for high risk renal transplant patients
2. Treatment of cell medicated rejection or combined cell and ABMR, Banff grade IB (if patient present in first year post transplant and biopsy revealed low chronicity index) or Banff grade II or III.
Side effects :
1. Infusion reactions (fever, chills, headache, diarrhea, hypotension, vomiting, may be ARDS)
2. Pancytopenia
3. Increase risk of infections especially CMV
4. Increase risk of EBV related PTLD
Mode of administration and dosage :
A- For Induction therapy
⦁ rATG is given intravenously in a dose of 1-2 mg/kg/d (starting intraoperatively before reperfusion of donor kidney) in combination with methylprednisolone in a dose of 7 mg/kg intraoperatively
⦁ if contraindicated basiliximab can be given
B- For acute rejection treatment
⦁ IV: 1.5 mg/kg/day for 4-6 days in combination with methylprednisolone at 3-5 mg/kg /d for 3-5
⦁ if contraindicated alemtuzumab can be given
General rules:
⦁ The optimal cumulative dose is not set till now but dose < 3 mg /kg and > 6 mg/kg are not recommended, use lower cutoff for low risk patients and higher cuttoff for high risk patients
⦁ Daily CBC is done if WBCS < 2000 microL or platelets < 75000microL the next dose is skipped, and If WBCS between 2000-3000 microL or platelets between 75000-100000 microL the next dose is halved.
⦁ No dosage adjustment required for renal or hepatic impairment
⦁ The drug is supplied in the form of 10 ml vial containing 25 mg rATG
⦁ First dose should be infused over at least 6 hrs , subsequent doses may be infused over at least 4 hours.
⦁ Should be infused through a high-flow vein (central line)
⦁ Premedication with corticosteroids, acetaminophen and antihistamine is recommended 1 hour prior to infusion
⦁ If severe reaction occur stop and if mild reaction occur decrease the rate of infusion
OKT-3
Mechanism of action :
⦁ OKT-3 is a monoclonal AB which binds to lymphocyte CD3 complex leading to rapid lysis.
⦁ It is the first monoclonal AB used in transplantation
Indications :
Approved only in the treatment of acute allograft rejection not for induction, although it is used for induction by few centers in pediatric clinical transplantation.
Side effects :
⦁ First dose infusion reaction (cytokine release syndrome) including (fever, chills, headache, diarrhea, hypotension, vomiting, and may cause severe pulmonary edema) infusion reaction occur in > 2 third of the patients after 30-60 mins of infusion
⦁ Anaphylactic reactions same manifestation of cytokine release syndrome but usually occur earlies after 10 min.
⦁ Formation of anti-OKT3 antibodies leading to resistance to treatment which is more common in children
⦁ CNS side effects including headache, seizures, aseptic meningitis, encephalopathy, cerebral edema, fatal cerebral herniations due to cerebral edema
⦁ Increase risk of infections especially CMV
⦁ Increase risk of EBV related PTLD
Mode of administration and dosage :
⦁ OKT-3 is a monoclonal AB which binds to lymphocyte CD3 complex leading to rapid lysis.
⦁ It is the first monoclonal AB used in transplantation
⦁ Premedication with corticosteroids, acetaminophen and antihistamine is recommended 1 hour prior to IV shot.
I prefer to use rATG because of the following :
1- The effect of rATG is comparable to OKT3
2- Side effects of OKT3 are more serious than those experienced by r ATG especially cytokine release syndrome (pulmonary edema) and CNS side effects (cerebral edema)
3- OKT3 is given by bolus injection so no action could be done as decreasing or stopping infusion like rATG.
REFERANCES
1. Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol. 2015;2(5):e194-203
2. Brennan DC, Flavin K, Lowell JA, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients [published correction appears in Transplantation 1999;67(10):1386]. Transplantation. 1999;67(7):1011-1018
3. Kutzler HL, Ye X, Rochon C, Martin ST. Administration of antithymocyte globulin (rabbit) to treat a severe, mixed rejection episode in a pregnant renal transplant recipient. Pharmacotherapy. 2016;36(4):e18‐e22.
4. Adair JC, Woodley SL, O’Connell JB, et al. Aseptic Meningitis following Cardiac Transplantation: Clinical Characteristics and Relationship to Immunosuppressive Regimen. NeuChatenoud L, Legendre C, Ferran C, et al. Corticosteroid Inhibition of the OKT3 – Induced Cytokine-Related Syndrome – Dosage and Kinetics Prerequisites. Transplantation 51:334–338, 1991.
5. Cockfield SM, Preiksaitis J, Harvey E, Jones C, Herbert D, Keown P, and Halloran PF, et al. Is Sequential Use of ALG and OKT3 in Renal Transplants Associated with an Increased Incidence of Fulminant Post Transplant Lymphoproliferative Disorders? Transplant. Proc. 23:1106–1107, 1991.rology 41:249–252, 1991.
Well done
ATG is a polyclonal IgG obtained from sera of horses & rabbits which immunized with human lymphocytes. After administered by IV infusion it will induce rapid T-cells depletion through different mechanisms:
Also ATG can control B cells activation & Ab formation through:
ATG used as induction therapy for sensitized pre transplant patients & as treatment of acute cellular rejection, steroid resistant rejection & acute ABMR. Its side effects include low grade fever, arthralgia & cills but severe reaction is rare.
OKT3: it is a murine monoclonal Ab of IgG2A against CD3 part of Cell receptor, it block T cell function but has limited effect on other tissues & cells.
It given by IV route & need premedication with steroid, acetaminophen & diphenhydramine to prevent the side effects like cytokine release syndrome & pulmonary edema, so it should be avoided in hypervoleumic patients although it can occur in euvoleumic patients.
It used for prevention & treatment of acute rejection ( especially steroid resistant rejection).
References :
OKT3
A murine monoclonal antibody.
mechanism of action of
Muromonab CD3 (OKT3): a murine monoclonal antibody directed against the CD3 antigen on mature peripheral human T cells, blocks T cell function. A rapid decrease in T-lymphocytes occurs within a few minutes after administration of muromonab CD3.
indication:
1.This antibody is used mainly in renal, liver and heart transplant:
2.It is also used in T cells acute lymphoblastic leukemia.
Dosage:
It is administered in a dose of 5 mg through IV push every day for 10–14 days (Hooks et al., 1991)
side effec
contraindication
The drug is contraindicated in condition like heart failure, epilepsy, allergy pregnancy and uncontrolled arterial hypertension
THYMOGLOBULIN
Thymoglobulin® (anti-thymocyte globulin [rabbit]) is a purified, pasteurized, immunoglobulin G, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic antibodies directed against antigens expressed on human T-lymphocytes.
mechanism of action
Dosage
About 40% patients treated with thymoglobulin (mean of 6 doses at 1.5 mg/kg/day) recover more than 50% of initial lymphocyte count at 3 months
[Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, Dolan S, Kano JM, Mahon M, Schnitzler MA, Woodward R, Irish W, Singer GG:
A randomized, double-blinded comparison of thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.
Transplantation 1999;67:1011-1018.].
indication
{Thymoglobulin and Its Use in Renal Transplantation: A Review , Thiyagarajan U.M.a · Ponnuswamy A.b · Bagul A.c ; Am J Nephrol 2013;37:586-601 https://doi.org/10.1159/000351643}
Side Effects
1.Acute and early reaction: will present as cytokine release syndrome which is characterised by anaphylaxis, fever, chills/rigors, dyspnoea, nausea/vomiting, diarrhoea, hypotension or hypertension, malaise, rash, and/or headache which usually can be managed by stopping infusion and epinephrine.
2.Severe reaction includes cardiorespiratory dysfunction including hypotension, pulmonary oedema, myocardial infarction, tachycardia and rarely death.
3.Delayed reactions usually present as (i) serum sickness and (ii) infections.
OKT3
It is muromonab-CD3 murine monoclonal antibody of immunoglobulin 2A clones to the CD3 portion of the T-cell receptor. It is the first monoclonal antibody.
Mechanism of action: it is antibody directed against CD3 which molecule part from multicomplex molecule on the surface of mature T cell close to TCR ( T cell receptor), there is association between CD3 and TCR , so the block of CD3 will affect T cell activation. It blocks function and generation of T cells.
After initial dose of OKT3 , T lymphocytes that express CD3 disappeared soon , it cause opsonization/internalization of CD3. CD3 will reappear back after 48 hrs of discontinuation of OKT3.
Side effects: Cytokine release syndrome
( fever, hypotension, dyspnea, headache), pulmonary edema in hypervolemic or even euvolemic patients may occur.
It is immunogenic; antibodies can be formed against it so subsequent doses will be ineffective in most of cases.
PTLD (post-transplant lymphoproliferative disease).
indications: Induction immunosuppression.
Treatment of primary acute rejection.
Treatment of steroid resistant rejection.
Used in ATG resistant rejection.
Can be monitored by CD3 antigen assay.
Mode of administration: Premedication should be given to guard against cytokine release syndrome like steroid, acetaminophen, and diphenhydramine.
Given by 2hrs iv infusion.
References:
D J Norman. Mechanisms of action and overview of OKT3. Ther Drug Monit. 1995 Dec;17(6):615-20.
I J ten Berge , K J Parlevliet, M H Raasveld, S Buysmann, F J Bemelman, P T Schellekens. Guidelines for the optimal use of muromonab CD3 in transplantation. BioDrugs.1999 Apr;11(4):277-84.
Thymoglobulin
It is polyclonal rabbit antithymocyte globulin, it is a mixture of different antibodies specificities.
Also there is horse ATG (hATG).
Mechanism of action:
It interact with different antigens involved in immune response, and adhesion molecules.
It is T cell depleting agent , cause complement dependent cell lysis in the blood and apoptosis of T cells in lymphoid tissues.
It modulate cell surface markers and adhesion molecules so prevent leucocytes adhesion to endothelium.
This depletion of effector T cells will increase in Treg numbers , so facilitate immunosuppression or inhibitory action of immune system.
side effects:
Cytokine release syndrome
Pancytopenia.
PTLD
indications:
Induction immunosuppression.
Treatment of allograft rejection and graft versus host disease GVHD.
Treatment of aplastic anemia.
Mode of administration:
Given by IV infusion over 4-6 hrs with premedication to guard aginst cytokine release syndrome.
References:
Andreea Delia Moiceanu, Anca Maria Popp, Ioanel Sinescu. Thymoglobulin – new approaches to optimal outcomes. J Med Life. 2009 Jul-Sep; 2(3): 319–324.
Mueller, Thomas F. Mechanisms of Action of Thymoglobulin. Transplantation: December 15, 2007 – Volume 84 – Issue 11S – p S5-S10.
I prefer ATG/ Thymoglobulin
Thank you for your reply
What you prefer ATG?
yes
OKT3 ( muromonab) is a murine monoclonal antibody of IgG2 isotype, it acts by targeting CD3, block both the generation and function of effector T cells. it react with peripheral peripheral blood T cells, body tissue T cells but not other hematopoietic elements.
it is used for induction and treatment of acute allograft rejection,it’s action lasts for 7 days. side effects include cytokine release syndrome and pulmonary edema ,PTLD, aseptic meningitis, seizure & infection. it is immunogenic and 50% of the patients will develop antibodies against it after a course of treatment and this has prevent the use of it as a maintenance therapy. it is administered via IV route.
It is no longer used because of life threatening first dose reaction.
ATG is a polyclonal IgG produced from the sera of rabbit or horse, after infusion, ATG reacts against a variety of targets including red blood cells, neutrophils, dendritic cells and platelets in addition to T cell depletion. also it causes rapid expansion of Tregs.
ATG is used for induction therapy and treatment of steroid resistant rejection.
side effects include cytokine release syndrome, infection, malignancy and hematological abnormalities like anaemia, thrombocytopenia & leukopenia.
ATG is given by IV infusion.
References:
OKT3 or Muromonab-CD3 is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. In 1986 Muromonab was the first approved monoclonal antibody, by FDA, to be used in humans.
As mentioned is the previous clinical scenario, T lymphocytes activation begins with signal 1 with the binding of TCR/CD3 to antigenic peptides presented by the APC which then triggers the activation in tyrosine phosphorylation of multiple cellular proteins and subsequent activation , proliferation and differentiation of T lymphocytes. OKT3 blocks T cell function by modulating CD3 and the T cell receptor from the T cell surface.
In 2010, Muromonab was withdrawn from the market by the manufacturer because of numerous side effects and available alternatives with better tolerability and less side effects.
Muromonab-CD3 is approved for the therapy of acute, glucocorticoid-resistant rejection of allogeneic renal, heart and liver transplants. It is not approved for prophylaxis of transplant rejection, although a 1996 review has found it to be safe for that purpose.
The use of OKT3 was associated with several side effects. The first infusion of OKT3 could be associated with activation of T cells with subsequent release of cytokines like tumor necrosis factor and interferon gamma. This cytokine release syndrome is associated with fever, chills, nausea, vomiting, skin manifestations, and could lead to life-threatening conditions . When used, premedication with acetaminophen, diphenhydramine and steroids is needed to minimize the risk of CRS.
Other adverse effects include leucopenia, aseptic meningitis and encephalopathy.
The usual dose is 5 mg administered as an intravenous bolus over 2-4 minutes daily for 10-14 days.
Thymoglobulins
Thymoglobulin acts as a rapid T-cell-depleting agent in both the blood and peripheral lymphoid tissues. The major pathways for T-cell depletion are complement-dependent cell lysis in the blood compartment and apoptotic cell death in the lymphoid tissues. There are 2 forms of antithymoglobulins depending on the origin of antibodies.Thymoglobulin is a polyclonal antibodies that are generated in rabbits and used as immunosuppressive therapy. Although there is no generic formulation, it is commonly referred to as rabbit antithymocyte globulin, or rATG. Another polyclonal antibody, Atgam, is a purified gamma globulin solution. It is obtained by immunization of horses with human thymocytes. Rabbit antithymocyte globulin is more effective than Atgam in lowering the acute rejection rate. That’s why it is commonly used in the induction immunosuppression in high risk patients.
ATG use, as OKT3, can induce cytokine release syndrome, and is associated with an increase in the risk of post-transplant lymphoproliferative disorder. However, this association could be altered with the use of lower doses. Temporary depletion of the T-cell population at the time of the transplant also risks delayed acute rejection, because of delayed rebound activation of T cells. There is also evidence to that inducion immunosuppression with rATG could create conditions in the patient’s immune system favorable to the development of immunological tolerance.
ATG is given intravenously at rate of 1.5 mg/kg in 0.9% NaCl given over 6 – 8 hours in the perioperative period.
A study on the acute steroid-resistant rejection episodes treated with set doses of anti-thymocyte globulin (ATG) or anti-CD3 monoclonal antibody (OKT3), with the monitoring of T lymphocytes showed that administration of ATG and OKT3 is safe and seems effective in treatment of ASRR.
References:
-Midtvedt K, Fauchald P, Lien B, et al. (February 2003). “Individualized T cell monitored administration of ATG versus OKT3 in steroid-resistant kidney graft rejection”. Clinical Transplantation. 17 (1): 69–74.
– Mutschler, Ernst; Gerd Geisslinger; Heyo K. Kroemer; Monika Schäfer-Korting (2001). Arzneimittelwirkungen (in German) (8 ed.).
-Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 937. ISBN 3-8047-1763-2.Smith, S. L. (1996). “Ten years of Orthoclone OKT3 (muromonab-CD3): a review”. Journal of Transplant Coordination. 6 (3): 109–119, quiz 119–
-Abdi, Reza; Spencer Martin; -Steven Gabardi (2009). “Immunosuppressive Strategies in Human Renal Transplantation – Induction Therapy” (PDF). Nephrology Rounds. 7 (4)
-Mahmud, Nadim; Dusko Klipa; Nasimul Ahsan (2010). “Antibody immunosuppressive therapy in solid-organ transplant Part 1”. mAbs. 2 (2): 148–156.
-Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006; 355:1967.
-Hardinger KL, Brennan DC, Schnitzler MA. Rabbit antithymocyte globulin is more beneficial in standard kidney than in extended donor recipients. Transplantation 2009; 87:1372.
-Miller JT, Collins CD, Stuckey LJ, et al. Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression. Pharmacotherapy 2009; 29:1166.
-Wiland AM, Fink JC, Weir MR, et al. Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial. Transplantation 2004; 77:422.
-Cassuto JR, Levine MH, Reese PP, et al. The influence of induction therapy for kidney transplantation after a non-renal transplant. Clin J Am Soc Nephrol 2012; 7:158.
In your practice (in your opinion if you are not practising) what are the indications of ATG induction? and what is the dose and the duration of treatment?
1) historical crossmatch positive
2)nil match for HLA A and B antigens
3)deceased donor transplant
4)CDC negative, FCXM positive, DSA negative
5)CDC negative, FCXM positive, DSA positive with MFI <1000,1000-10000(along with desensitization)
6)CDC negative, FCXM negative, DSA positive with MFI <1000,1000-10000(along with desensitization)
dose- (total 3mg/kg)1.5mg/kg each on POD 0 and POD 2.
What are the indication of ATG in acute rejection (antibody mediated and cell mediated)?
acute TCMR- no indication
steroid resistant acute TCMR- ATG is used for rejections that do not respond to corticosteroids.
other options- MMF, rituximab, IvIg, plasmapheresis, tacrolimus
recurrent acute cellular rejections- ATG
acute ABMR- when ABMR is associated with severe TCMR ATG could be combined with other treatment modalities.
Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects– Jamal Bamulid et al
mechanism of actionOKT3- is a murine monoclonal antibody against CD3- Rapid (within 1 hour) activation and cytokine release from, all CD3 + cells- Subsequent internalization of the T-cell receptor and T-cell unresponsiveness-Clearance of >90% CD3 cells from the circulation within 24 hours.
Repeated administration is required to maintain CD3 depletion.
ATG-includes antibodies against components of the T-cell receptor (CD3, CD4 and CD8),HLA class I and II molecules, cytokine receptors (including CD25) and adhesion molecules. Leads to T-cell activation, clearance of T cells from the circulation, inhibition of both co-stimulatory and proliferative signals, and inhibition of cell adhesion and migration.
T-cell depletion following ATG may persist for months or years.
indicationOKT3-treatment of severe or resistant rejection
ATG- as induction therapy in high immunological risk pts, deceased donor transplants, historical crossmatch positive, nil match for HLA A and B antigens,
CDC negative, FCXM positive, DSA negative
CDC negative, FCXM positive, DSA positive with MFI <1000,1000-10000(along with desensitization)
CDC negative, FCXM negative, DSA positive with MFI <1000,1000-10000(along with desensitization)
steroid resistant TCMR, severe mixed TCMR and ABMR
side effect OKT3-
anaphylaxis
cytokine release syndrome
diarrhoea and vomiting
dyspnoea and bronchospasm
severe non cardiogenic pulmonary edema
headache
aseptic meningitis
rarely encephalopathy, seizures
increased infections
increase in PTLD by 2-3 fold.
ATG-
anaphylaxis
cytokine release
decreased platelets and leucocytes
increased infections
increase in PTLD
mode of administrationOKT3 –
Precautions
• Do not give OKT3 if there is untreated infection or poorly controlled epilepsy.
• Ensure that the patient is not fluid overloaded.
• Weight within 1–2kg of dry weight, No pulmonary edema on CXR, and minimal peripheral edema
• Normal BP.
• Pre-medication to be given 30–60 minutes before the first 2 doses of OKT3-
• IV methylprednisolone (250mg if <60kg, 500mg if >60kg)
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Dose
• Following pre-medication, OKT3 is given as an IV bolus of 5mg (2.5mg for children <30kg) into a peripheral vein.
Given daily for 10 days .
Monitoring
Flow cytometry to identify CD3+ cells, If CD3 cells >0.05×10 /L then ↑ dose to 10mg daily
ATG
Precautions
Cytokine release leading to fever and rigors is common after the first one or two doses of any ATG preparation.
• Do not give Thymoglobulin if there is untreated infection, ↓platelets or ↓WCC.
• For the first dose, ensure that the patient is not fluid overloaded.
• Pre-medication to be given 60 minutes before each dose of Thymoglobulin :
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• Ensure prophylaxis against PCP, CMV and oral candidiasis.
Administration
• Thymoglobulin is usually diluted into 500ml 0.9% NaCl (the final concentration should be <0.5mg/ml).
• Thymoglobulin must be given into a central vein
• Following pre-medication, Thymoglobulin is given as an IV infusion over >6 hours (first dose) or >4 hours (subsequent doses).
• decrease the infusion rate by 50% if the patient experiences infusion-related symptoms of cytokine release.
Monitoring
• Measure CBC daily
• If platelets <75×10 /L → half dose, <50×10 /L → omit
• If WCC <3.0×10 /L → half dose, <2.0×10 /L → omit
• Measurement of CD3 T cells by flow cytometry daily, If CD3 count <0.05×10 /L then no Thymoglobulin is required that day.
Dose
• Induction therapy—6mg/kg, with the first dose of 1.5mg/kg administered intra-operatively, and subsequent doses daily, or on postoperative days 1, 3 and 5 or
3mg/kg with 1.5mg/kg on POD 0 and POD2.
• Rejection therapy—typically 1.5mg/kg daily for 10–14 days, with daily dose determined by monitoring of CBC± CD3 cell count.
Many alternative regimens exist.
Oxford Handbook of transplantation.
OKT3:
Monoclonal Ab ,Blocks CD3 function in T lymphocytes leads to internalization of the T-cell receptor and T-cell unresponsiveness , With Clearance of >90% of CD3 cells from the circulation within 24 hours
Indication:
In induction therapy and in the treatment of acute rejection.
Adverse effects:
Anaphylaxis
Cytokine release syndrome
Increase infections
Increase in post-transplant PTLD
Administration of OKT3:
Premedication (IV methyl prednisolone,IV H1 antagonist ,paracetamol PO).
Not used nowadays due to severe side effects
Thymoglobulin: ATG
Mechanism of action
Polyclonal Ab with cytotoxic effect against a variety of T-cell markers leading to depletion of prepheral lymphoctyes and can causes rapid sustained expansion of CD4+, CD25+, FOXP3 T reg cells involved in graft tolerance.
Indication:
Same as OKT3
Adverse effects:
Anaphylaxis with Cytokine release
Decrease WBC and platelet
Increase infections
Increase in PTLD
Thank you Mohamad just please remember as per your last sentence
OKT3 is really not at all safe it is out of use for quite some time. It is included in the discussion just for comparison.