2. Memory cells constitute a challenge in transplant immunology. They are resistant to co-stimulation blocking agents. They are long-lived and require minimal stimulation to become activated.
- Please reflect on the above statement emphasizing the role played by the memory cells in transplantation
- Discuss the strategies attempted to suppress their effect.
Dear All
Thanks for your contributions
Yes, memory cells are difficult to suppress with immunosuppressive drugs, can be activated quickly and easily (less dependent on co-stimulation).
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
1- Please reflect on the above statement emphasizing the role played by the memory cells in transplantation;
1-Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade.
2-Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells. In the absence of any prior exposure to allogeneic MHC molecules, endogenous alloreactive memory T cells are regularly generated through microbial infections (heterologous immunity).
3-Alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation.
2- Discuss the strategies attempted to suppress their effect;
1-Lymphoablation;
Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts .
2-Costimulatory Blockade;
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors . As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that pre sensitized T cells could account for some belatacept-resistant rejection episodes.
3-Limiting Trafficking of Alloreactive Memory T Cells;
a short course of integrin blockade may be instrumental in controlling T cell memory while avoiding side effects of long-term treatments.
Reference;1- Neujahr DC, Chen C, Huang X, Markmann JF, Cobbold S, Waldmann H, et al. Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J Immunol (2006) 176(8):4632–9. doi:10.4049/jimmunol.176.8.4632
PubMed Abstract | CrossRef Full Text | Google Scholar
2-. Zeevi A, Husain S, Spichty KJ, Raza K, Woodcock JB, Zaldonis D, et al. Recovery of functional memory T cells in lung transplant recipients following induction therapy with alemtuzumab. Am J Transplant (2007) 7(2):471–5. doi:10.1111/j.1600-6143.2006.01641.x
PubMed Abstract | CrossRef Full Text | Google Scholar
3-. Haanstra KG, Sick EA, Ringers J, Wubben JA, Kuhn EM, t Hart BA, et al. No synergy between ATG induction and costimulation blockade induced kidney allograft survival in rhesus monkeys. Transplantation (2006) 82(9):1194–201.
PubMed Abstract | Google Scholar
4-. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant (2005) 5(3):465–74. doi:10.1111/j.1600-6143.2005.00759.x
5-. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobert E, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant (2005) 5(3):443–53. doi:10.1111/j.1600-6143.2005.00749.x
PubMed Abstract | CrossRef Full Text | Google Scholar
6- Rostaing L, Vincenti F, Grinyo J, Rice KM, Bresnahan B, Steinberg S, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant (2013) 13(11):2875–83. doi:10.1111/ajt.12460
PubMed Abstract | CrossRef Full Text | Google Scholar
7-Vincenti F, Larsen CP, Alberu J, Bresnahan B, Garcia VD, Kothari J, et al. Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients. Am J Transplant (2012) 12(1):210–7. doi:10.1111/j.1600-6143.2011.03785.x
Differentiation from effector lymphocytes to memory cells depends on IL7 and IL 15.T memory cells are of 2 main subsets central ;Tcm expressing CCR7 and effector ;Tem cells expressing CXCR3.They have higher frequency and longer life span together with wide migration and lower threshold of activation. They generate recall immune response. with is partially dependent on classic co stimulatory response .So, resistant to inhibition by CTLA4 -Ig; BELATACEPT and patients receiving it has severe acute rejection more than those on Tac. .So, they are formidable obstacle to Tx .They cause higher incidence of AR. In recovery from lymphopenia after using deleting agents ,late CNI withdrawal is not safe due to T memory cells.
REFERENCES
Handbook of kidney transplantation, Danovitch, GM, Sixth edition
Memory T cells referred to subpoplation of T cells with antigen priming effect that persist and can trigger denovo alloimmune response due to reexpousure to variable anitgenes they induce the expression of adhesion molecule with out the need of the costimulation ,Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens
Maintenace IS with CNI can effectively control the expression of T memory cells but with the risk of chronic allograft toxicity and nephropathy, lymphocyte deleting agents like ATG and almetuzemab induction agents costimlatory blockers agent can deplet allospecificT cells but not the memory T cells
References:
1-Memory T cells in organ transplantation: progress and challengesJaclyn R Espinosa 1 , Kannan P Samy 2 , Allan D Kirk Nat Rev Nephrol
Actions 2016 Jun;12(6):339-47 .
Please reflect on the above statement emphasizing the role played by the memory cells in transplantation
Both T & B cells exhibit memory response.
Memory Cells are formed by either one of the following pathways:
1- Direct exposure to MHC during a sensitization event such as blood transfusion, pregnancy or previous transplantation.
2- Exposure to proteins of bacteria or environmental antigens with similar molecular structure of alloantigens.
Memory cells have increased expression of adhesion molecules and decreased need for co-stimulation, leading to resistance to conventional immunosuppression and co-stimulation blockade, leading to an important role in graft rejection.
Memory CD4+ T cells, upon reactivation, give rise to effector CD4+ T cells which in turn activate CD8+ T cells leading to graft rejection.
Activation of memory CD4+ T cells leads to effector CD4+ T cells which activate CD8+ T cells mediating cytotoxicity and ending with graft rejection.
Memory helper T cells provide help for B cells to produce DSA leading to ABMR.
There are several subtypes of memory T-cells.
Memory B cells require re-stimulation to contribute to the memory response, but can proliferate quicker than naive B cells and give rise to new memory population, and they don’t exhibit any effector function.
Strategies attempted to suppress the effects of Memory T cells include:
1- Lymphoablation:
A1- ATG and Almetuzumab (anti-CD52 mAb) are used as induction therapy in sensitized patients.
Some memory T cells are still less susceptible to these drugs than naive T cells, then they develop resistance to these depleting agents and become responsible for acute rejection.
2- T cell costimulation blockade:
Belatacept (blocks CD28), has been shown to improve graft survival rates but has increased acute cellular ejection as memory T cells are more resistant to it.
3- Manipulating metabolic pathways: CNIs and mTOR inhibitors affect differentiation and activation of memory T cells.
4- Under trial and research:
a- Alefacept which targets memory/effector T cells is shown improve graft survival by depleting effector memory cells resistant to costimulatory blockade in nonhuman primates.
b- Siplizumab (humanized BTI-322) has been used as a part of tolerance inducing protocol with successful management of HLA mismatched kidney transplant recipients without maintenance IS.
c- AMP activated protein kinase inhibition and aquaporin 4 inhibition are the strategies in focus for further research to suppress memory T cells.
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you consider him sensitised?
He is sensitized recipient because of previous 2 transplants, however no desensitization is required because negative cross match and absent DSA.
He will need ATG for induction
Tacrolimus, MMF and steroids for maintenance.
Monitor DSA post-Transplant.
Memory T cells are a subset of t cells that last after activation and are characterized by release of TH1 and TH2, also, they show response to stimulation by APC and anti cd 2 Antibodies.
Memory cells are long-lived immune cells capable of recognizing foreign particles they were previously exposed to These immune cells do not respond immediately when it first encounters an antigen but facilitates a more rapid secondary response when the antigen is encountered on a subsequent occasion.
It difficult to control it but in my opinion
Aggressive induction immunosuppressant by deplititing agent as ATG and good maintenance immunosuppressant ( mmf-tacrolimus-cortisol) can minimize it’s effect and make more control.
Yes as previous 2 failed graft and previous exposure to different AG
Memory Cells
Although there is limited knowledge of how memory T cells are gener-
ated or maintained, these cells are an important component of the
immune response to infectious pathogens. In clinical transplantation,
previous sensitization to alloantigen with formation of memory cells
is associated with increased risk for rejection and premature graft failure.
Memory responses to alloantigen frequently occur at the time of blood
transfusion, pregnancy, and transplantation. However, alloantigen
memory responses can develop as a result of antigen cross-reactivity
during response to infection (heterologous immunity), but also by
normal proliferation in response to lymphopenia induced by leukocyte-
depleting agents in transplant recipients.
The principle of immunologic memory is that the immune response
to a previously encountered antigen is swifter and more effective than
the response to a new antigen. Memory cells are more easily activated
than naïve T cells, with lower requirement for costimulation, and in
addition, produce more cytokines. Furthermore, there is an increase in
antigen-specific T cell frequency after exposure to a given antigen. Finally,
exposure to antigen leads to a refinement of the antibody repertoire,
resulting in a more effective memory response. Effector memory T cells
are specialized for quickly entering inflamed tissues because they can
rapidly mature into effector T cells and secrete larger amounts of cyto-
kines after restimulation. Central memory T cells likely remain in the
SLOs and do not produce as much cytokine.25 Memory cells are believed
to persist after an initial immune response through expression of the
antiapoptotic genes Bcl-2 and Bcl-xL, which are induced primarily by
IL-2 and CD28 stimulation, although IL-15 also may provide survival
signals. Long-term memory cell survival is likely a function of periodic
interactions with self-MHC:peptide complexes on APCs (i.e., homeo-
static proliferation).
Ref-Willinger T, Freeman T, Hasegawa H, et al. Molecular signatures
distinguish human central memory from effector memory CD8 T cell
subsets. J Immunol. 2005;175:5895–5903.
Sensitisation events include ; pregnancy, blood transfusion, and previous transplants. So by definition this gentleman is already sensitised due to his previous transplants. Solid phase assay is important test here due it is high sensitivity and ability to detect pre-sensitisation from previous graft, allow the avoidance of those HLA markers on subsequent grafts.
Because this patient is sensitised he is automatically high risk.
Crossmatch negative ,therefore no need for desensitization protocol. However he needs augmented immunosuppression( induction by ATG or alemtuzumab), protocol biopsy, post-transplant monitoring for De Novo DSA, high levels of maintenance immunosuppression. This kind of patient may very close attention because the other side of the coins are high risk of infections , malignancy, and cardiovascular complications.
Both cellular and humoral adaptive immune responses making long-lived memory T and B cells the central players in immunological memory as a rapid and effective response against a second exposure with the same antigen.
Alloreactive memory T and B cells may arise as a result of exposure to allogeneic human leukocyte antigens (HLA) through blood transfusions, pregnancies or previous transplantations. Interestingly, individuals who have never been exposed to alloantigens may as well harbor alloreactive memory as a result of heterologous immunity.
These patients are not only difficult to pair with a crossmatch negative donor in order to be transplanted but are also more susceptible to develop T cell and/or antibody-mediated acute and chronic rejection unless special allocation algorithms or desensitization treatments are used . In kidney transplantation current practice focuses on the presence or absence of plasma cell-derived donor HLA directed antibodies (DSA) and HLA matching which ignores the potential contribution of alloreactive memory cells to graft rejection
Alloreactive T Cells:
Is the central players in mediating allograft rejection. They contribute to both acute and chronic rejection depending on the pathway utilized to recognize donor antigens (both major and minor histocompatibility antigens). T cells recognize alloantigens through the direct, indirect or semi-direct pathway .
The direct pathway alloimmune response is stronger, likely due to the high frequency of direct pathway alloreactive T cells .
.
The indirect pathway of T cell allorecognition is considered to be long-lasting and particularly important in the development of chronic allograft rejection because of exclusive cognate help provided by indirect CD4 T cells to alloreactive B cells leading to alloantibody production. Additionally, indirect alloresponses against minor histocompatibility antigens may also occur. However, in comparison to the enormous polymorphism of MHC, indirect allorecognition of minor antigens appears to be less relevant
the semi-direct pathway, recipient T cells recognize intact allo-MHC similar to direct way of allorecognition but on the surface of self APC that have acquired allo-MHC by various means including cell to cell contact or exosomes, suggesting a role for both direct and indirect allorecognition pathways in chronic alloimmune responses
Alloreactive B Cells:
Humoral alloimmunity can lead to antibody mediated rejection (ABMR), of which the chronic form is the leading cause of graft loss in kidney transplantation .. Interaction between alloreactive T and B cells plays a key role in the generation of full-blown humoral alloimmune responses. Help from indirect pathway CD4 T cells is essential for generating antibodies against HLA, as with conventional protein antigens.
Amir AL, D’Orsogna LJ, Roelen DL, van Loenen MM, Hagedoorn RS, de Boer R, et al. Allo-HLA reactivity of virus-specific memory T cells is common. Blood. (2010) 115:3146–57. doi: 10.1182/blood-2009-07-234906
Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN,
Lechler RI. The role of the allograft in the induction of donor- specific T cell hyporesponsiveness. Transplantation. (2001)
72:480–5. doi: 10.1097/00007890-200108150-00020Emerson RO, Mathew JM,
Konieczna IM, Robins HS, Leventhal JR. Defining the alloreactive T cell repertoire using high-throughputsequencing of mixed lymphocyte reaction culture. PLoS ONE. (2014)9:e111943. doi: 10.1371/journal.pone.0111943.
Gould DS, Auchincloss H Jr. Direct and indirect recognition: the roleof MHC antigens in graft rejection. Immunol Today. (1999) 20:77–82. doi: 10.1016/S0167-5699(98)01394-2
Zhu L, Fu C, Lin K, Wang Z, Guo H, Chen S, et al. Patterns of early rejection in renal retransplantation: a single-center experience. J Immunol Res. (2016) 2016:2697860. doi: 10.1155/2016/2697860
Gray D. A role for antigen in the maintenance of immunological memory. Nat Rev Immunol. (2002) 2:60–5. doi: 10.1038/nri706.
Hammarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med. (2003) 9:1131–7. doi: 10.1038/nm917Netea .
Wehmeier C, Karahan GE, Krop J, de Vaal Y, Langerak-Langerak J, Binet
I, et al. Donor-specific B cell memory in alloimmunized kidney transplantrecipients – first clinical application of a novel method. Transplantation.
(2019) 70:123–8. doi: 10.1097/TP.0000000000002909
MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. (2016) 352:aaf1098. doi: 10.1126/science.aaf1098.
. Marino J, Babiker-Mohamed MH, Crosby-Bertorini P, Paster JT, LeGuern C, Germana S, et al. Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci Immunol. (2016) 1:aaf8759. doi: 10.1126/sciimmunol.aaf8759
Lefaucheur C, Loupy A. Antibody-mediated rejection of solid-organ allografts. N Engl J Med. (2018) 379:2580–2. doi: 10.1056/NEJMc1813976
MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zuniga E, et al. Extrafollicular antibody responses. Immunol Rev. (2003) 194:8–18. doi: 10.1034/j.1600-065X.2003.00058.x
Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol. (2015) 15:149–59. doi: 10.1038/nri3802
Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. (2012) 30:429–57. doi: 10.1146/annurev-immunol-020711-075032
. Lavinder JJ, Wine Y, Giesecke C, Ippolito GC, Horton AP, Lungu OI, et al. Identification and characterization of the constituent human serum antibodies elicited by vaccination. Proc Natl Acad Sci USA. (2014) 111:2259–64. doi: 10.1073/pnas.1317793111
●The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
This patient is considered sensitised as he had 2 previous Tx although negative crossmatch and no DSA .
●Memory cells are long-lived immune cells capable of recognizing foreign particles they were previously exposed to (thus, the memory in their name). These immune cells do not respond immediately when it first encounters an antigen but facilitates a more rapid secondary response when the antigen is encountered on a subsequent occasion.
Examples of memory cells are memory B cells and memory T cells. Memory B cells are clones of a parent B cell that previously served as an antigen-presenting cell and then activated by a helper T cell to proliferate. As clones, the memory B cells bear the same B cell receptors as those of the parent B cell. Therefore, they would be able to detect the same antigen when re-exposed. Memory B cells produce more robust antibody-mediated immune response during re-infection.
Memory T cells are T lymphocytes that have the similar capability of recognizing foreign particles that they previously encountered. But unlike memory B cells, the memory T cells do not produce antibodies. Re-exposure to the pathogens causes them to clone themselves immediately and as such respond to the infection more stronglyMemory cells are long-lived immune cells capable of recognizing foreign particles they were previously exposed to (thus, the memory in their name). These immune cells do not respond immediately when it first encounters an antigen but facilitates a more rapid secondary response when the antigen is encountered on a subsequent occasion.
●Strategies attempted to decrease memory cells effect ?
1.
Lymphoablation
Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy.
2
Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors
3.
Limiting Trafficking of Alloreactive Memory T Cells
While preventing memory T cell entrance into graft tissue should improve transplant outcome, the attempts to neutralize chemokines or chemokine receptors such as CCR5 or CXCR3 did not live up to the initial expectations, most likely due to the redundancy of chemokine/receptor network. On other hand, reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) have been demonstrated to prolong allograft survival in experimental transplantation [reviewed in Ref. (133)]. Treatment with either anti-LFA-1 or anti-VLA-4 blocking mAbs prolonged skin allograft survival in a mouse model of costimulatory blockade-resistant rejection by memory CD8+ T cells (134). In another study, pretransplant treatment with anti-LFA-1 mAbs inhibited early infiltration of endogenous donor-reactive memory CD8+ T cells into cardiac allografts, and significantly prolonged allograft survival (135). These findings suggest that a short course of integrin blockade may be instrumental in controlling T cell memory while avoiding side effects of long-term treatments.
References
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328996/
After exposure to the primary antigen, long lived antigen-specific memory T and B cells are generated that are able to deliver a more rapid and higher magnitude immune response if the same antigen is encountered on a subsequent occasion.
Memory cells have lower threshold for activation and are less dependent on costimulation. As a consequence they are able to upregulate effector function and cytokine secretion more aggressively than naïve lymphocytes.
As the age increases, the proportion of T cells within peripheral T cell pool increases reflecting cumulative antigen exposure and that can be as high as 50% in adults.
In transplantation, evidence of prior sensitization to donor antigens is associated with increased risk of acute rejection and premature graft failure. Memory type responses towards alloantigens are frequantly due to exposure to alloantigens at the time of a previous blood transfusion, pregnancy or solid organ transplant.Curently it is recognized that memory-type responses may also be generated as a result of antigen receptor cross-reactivity (heterologous immunity) or by homeostatic proliferation of lymphocytes following an episode of lymphopenia such as are induced in transplant recipients by administration of leukocyte depleting agents.
As memory T cells are more resistant to the effects of CTLA4-Ig in animal transplantation models, it is possible that presensitized T cells could account for some belatacept-resistant rejectio. Terminally differentiated memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of CD28/B7 costimulation.it leads to increased numbers of both CD4+ and CD8+ CD28− memory T cells are associated with a poor outcome in renal and lung transplant.
Espinosa et al. reported a population of CD57+CD4+ T cells as potential mediators of belatacept-resistant renal allograft rejection which more common in patients with kidney failure. They express high levels of adhesion molecules CD2, LFA-1, and VLA-4, downregulate CD28, and produce IFNγ, tumor necrosis factor alpha (TNFα), and granzyme B consistent with effector phenotype.
Strategies attempted to suppress effect of memory cells
1. Lymphoablation
-antibody lymphocyte depleting agents is commonly used induction protocol in highly sensitised patients and recipient of ECD kidneys
-studies have shown synergistic effect between ATG lymphoablation and co-stimulatory blockade
2. Co stimulatory blockade
-CTLA 4-Ig -prevents signalling through CTLA4 and can have negative effects on generation and functions of Treg.
-others such as inhibition to ICOS/B7RP-1,CD 134/CD134L,CD70/CD27 or CD137/CD 137L will improve allograft survival even in sensitised patients.
References
Benichou, G., Gonzalez, B., Marino, J., Ayasoufi, K. and Valujskikh, A., 2017. Role of Memory T Cells in Allograft Rejection and Tolerance. Frontiers in Immunology, 8.
Memory cells include Tcells, Bcells and NK cells and macrophages. They play an important role for immunity against infectious pathogens but can mediate graft rejection or loss. They can promote adhesion molecule expression without co-stimulation requirement. So, they show rapid response when expose to prior antigens. Memory T cells cross-react with similar antigens or even cause de novo alloimmunity which prevents from allograft integration. Since memory Tcells lack costimulatory mechanism, its blockage is not effective in their inhibition. They have abundant adhesion molecules that makes their easy attachment to transplant. Memory T cells expand rapidly when cross-react with alloantigenes which is independent of lymphoid tissues. Ischemia leads to generation of ROS and DAMPs that activates memory Tcells. These cells also respond to complement receptors with rapid recall. ATG and alemtuzumab do not deplete memory Tcells as effective as naïve cells. Alemtuzumab in combination with sirolimus and belatacept is associated with increased population of T REG and B REG cells and prevents rejection due to memory Tcells. CNIs and mTOR inhibitors may decrease memory Tcell activation. Treatments targeting adhesion molecules such as LFA-1 by efalizumab, VAL-4 by natalizumab may also be effective.
References:
1. Espinosa, J., Samy, K. & Kirk, A. Memory T cells in organ transplantation: progress and challenges. Nat Rev Nephrol 12, 339–347 (2016).
2. Chen, W., Ghobrial, R. M., & Li, X. C. (2015). The evolving roles of memory immune cells in transplantation. In Transplantation (Vol. 99, Issue 10).
thankyou Nasreen for an organised answer showing that you do understand all about those memory cells,some facts only to mention are :they are also B as well,their robust amplified multiplication does not need costimulation,Belatacept is not radical but will increase the Regs.,ATG and signal 1 inhibitors will stop there ignition by damping the activated effector Tcells .As they depend on adhesion molecules this is an area for action.
Memory T cell:
After initial exposure to antigens, native T cells proliferate extensively and differentiate into effector T cells capable of infiltrating inflamed tissues,destroying invading microorganisms.After the pathogen is cleared, most effector T cells undergo apoptotic cell death, leaving behind
a population of antigen- experienced memory T cells.The ability to produce a robust memory response seem to be imprinted in the course of initial T cell priming. Thus, CD4 T cells help or CD40/CD154 interactions during activation phase are required for functional secondary CD8 T cell responses to viral antigens.
Memory T cells are often defined on the basis of the expression of cell surface molecules, activation markers, and tissue homing receptors.
Some used marker of native T cell as CD62L and higher molecular weight isoforms of CD45, can be re-expressed on late memory T cells.
**What are the features that make memory T cells distinct from their native counterparts?
The obvious strength of memory T cell responses is in numbers. After the primary response has subsided, the host immune repertoire contains many more antigen-specific T cells than before antigen exposure. The increased frequency of memory T cells translates into amplified effector functions after reinfection with the same pathogen. T cell receptor (TCR) transgenic models made possible the precursor frequency-indepen- dent analysis of antigen-specific T cells at distinct stages of differentiation. This direct comparison demonstrated that memory T cells can be triggered by lower doses of antigen than nagive cells.
Memory T cell and existing anti rejection therapies:
~Lymphoablation:
Because the presence of donor-specific T cell memory is often associated with poor allograft outcome, nonspecific deletion or at least reduction in numbers of memory T cells should enhance graft survival. The majority of peritransplantation lymphoablative strategies in clinic are based on the use of whole body irradiation diation, antibody-mediated cell lysis, or immunotoxins. Although these approaches certainly have merit in promoting engraftment and lowering the risk for early acute rejection, recent studies in rodents, nonhuman primates, and human transplant patients have raised a number of concerns regarding the efficacy of lymphoablation on a memory T cell pool.
Conventional Immunosuppression
Transplant patients rely on life-long immunosuppressive drugs to prevent T cell activation and graft loss. However, despite effective control of early rejection episodes with better immunosuppressive protocols, the longterm outcome of organ transplants has not improved much in the past few decades. Given the unique features of memory T cells and their apparent involvement in rejection, it is important to determine whether commonly used immunosuppressive drugs interfere with the development and effector functions of alloreactive memory T cells.
~Conventional Co-Stimulatory Blockade:
Targeting co-stimulatory pathways to prolong allograft survival stems from the observation that optimal T cell activation, differentiation, and survival require engagement of several accessory cell surface molecules in addition to TCR signaling.The terms conventional and classical co-stimulation are generally used to describe the two most prominent and best studied co-stimulatory path- ways: CD28/B7 and CD154/CD40. Multiple studies in rodents demonstrated that interference with either one or both of these pathways inhibits donor-specific T cell responses and facilitates prolonged graft survival or even tolerance.
However, the same therapies were much less efficacious when applied to large animals and humans.
New approaches targeting memory T cell :
Alternative Co-Stimulation Molecules
Cell surface structures with co-stimulatory properties are not confined to CD28 and CD154, and a number of new T cell co-stimulatory molecules have been described.
Most of these alternative co-stimulatory molecules are expressed only upon T cell activation, suggesting a particularly important role in the effector/memory phases of T cell response rather than the initial T cell priming. Indeed, recent studies from several laboratories provide compelling evidence that memory T cells may rely on alternative co-stimulation for activation, survival, or effector functions.
~Growth Factor Limitation:
It is believed that homeostasis of mem- ory T cells is largely controlled by the common c-dependent cytokines IL-7 and IL-15. Although these cytokines display overlapping functions, IL-7 is important for maintaining cell survival, whereas IL-15 is necessary to drive homeostatic proliferation of memory CD8T cells.
In contrast, IL-7 seems to play a more important role than IL-15 for maintenance of CD4 T cell memory.Because IL-7 and IL-15 are members of the common family, the question arises whether other cytokines have a similar function. The role of IL-2 in memory T cell generation and persistence is controversial. Injection of IL-2 at the end of the primary immune response can prevent death of CD122hi CD8 effector cells. The injection of neutralizing anti–IL-2 mAb induces a marked expansion of memory CD8 T cells. The interpretation of such data is complicated because, in addition to IL-2 neutralization, anti–IL-2 antibody may either restrict IL-2– dependent CD25CD4 T regulatory cell , releasing memory T cells from the Treg-mediated suppression or
enhance the in vivo biologic activity of preexisting IL-2.
References:
1. Sprent J, Surh CD: T cell memory. Annu Rev Immunol 20: 551–579, 2002. 8. Suresh M, Whitmire JK, Harrington LE, Larsen CP, Pearson TC, Altman JD, Ahmed R: Role of CD28–B7 interactions in genera- tion and maintenance of CD8 T cell memory. J Immunol 167: 5565–5573, 2001.
9. Li J, Huston G, Swain SL: IL-7 promotes the transition of CD4 effectors to persistent memory cells. J Exp Med 198: 1807–1815, 2003
10. Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R: Selective expres- sion of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long- lived memory cells. Nat Immunol 4: 1191– 1198, 2003.
11. Dai Z, Konieczny BT, Lakkis FG: The dual role of IL-2 in the generation and mainte- nance of CD8 memory T cells. J Immunol 165: 3031–3036, 2000
12. Dooms H, Wolslegel K, Lin P, Abbas AK: Interleukin-2 enhances CD4 T cell mem- ory by promoting the generation of IL-7R alpha-expressing cells. J Exp Med 204: 547–557, 2007
13. Goldrath AW, Sivakumar PV, Glaccum M, Kennedy MK, Bevan MJ, Benoist C, Mathis D, Butz EA: Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8 T cells. J Exp Med 195: 1515–1522, 2002
14. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD: Interleukin (IL)-15 and IL-7 jointly regulate homeostatic prolifera- tion of memory phenotype CD8 cells but are not required for memory phenotype CD4 cells. J Exp Med 195: 1523–1532, 2258 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 2252–2261, 2007.
2. Swain SL, Agrewala JN, Brown DM, Jelley-
Gibbs DM, Golech S, Huston G, Jones SC, Kamperschroer C, Lee WH, McKinstry KK,
Roman E, Strutt T, Weng NP: CD4 T-cell
memory: Generation and multi-faceted
roles for CD4 T cells in protective immu- 2002
nity to influenza. Immunol Rev 211: 8–22,
2006.
3. Lefrancois L: Development, trafficking, and
function of memory T-cell subsets. Immu-
nol Rev 211: 93–103, 2006.
4. Janssen E, Tabeta K, Barnes MJ, Rut-
schmann S, McBride S, Bahjat KS, Schoen- berger SP, Theofilopoulos AN, Beutler B, Hoebe K: Efficient T cell activation via a Toll-interleukin 1 receptor-independent pathway. Immunity 24: 787–799, 2006.
Memory T cells ( antigen-experienced Tcells)are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters.
Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens.
This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated.
A defining hallmark of adaptive or acquired immunity is the ability to generate an anamnestic response a heightened responsiveness to successive antigen encounters which forms the basis of long-term immunity. This response is largely attributed to memory T cells, which have long-lasting survival properties, strong effector responses and the ability to quickly become activated in the periphery.
Following the initial characterization of four memory T-cell subsets on the basis of surface expression of CCR7 and CD45RA2, it has become recognized that the surface phenotype of a memory T cell is associated with distinct functional capabilities. The increasing ability to investigate defined T-cell subsets and their responses to secondary antigen exposure has facilitated the elucidation of the complex plasticity of memory T cells; the four classically described subsets have expanded tremendously over time. This broad spectrum of antigen-experienced cells presents a major obstacle to the stable acceptance of transplanted organs; memory T cells are crucial mediators of allograft rejection3. In this Review, we describe the generation of memory T cells, the phenotypic markers associated with the best-defined subsets, their postulated impact on allograft rejection, and immune management strategies to mitigate their effects.
***Co-stimulation:
Naive T cells require numerous signals to enter a program of differentiation. This requirement has probably evolved as a mechanism to avoid promiscuous or unnecessary immune activation. As well as the interaction between the antigen-presenting MHC and the TCR, which provides the specificity of the response, another well-studied mechanism is co-stimulation, such as that conferred by the interaction between the B7 protein on antigen-presenting cells and CD28 (also known as cytotoxic T-lymphocyte-associated protein 4) on T cells, which provides confirmation of appropriate context for the response .This second co-stimulatory signal on naive T cells is required for the production of IL-2, which helps to promote T-cell differentiation. TCR ligation in the absence of co-stimulation can result in antigen-specific T-cell anergy2.
Following differentiation, the expression of CD28 is markedly downregulated and the resulting memory T cells no longer require co-stimulation for secondary immune responses. Thus, the lack of CD28 expression is an important hallmark of an antigen-experienced cell in humans and non-human primates.
The requirement for co-stimulation in T-cell differentiation forms the basis of the development of therapeutic agents designed to block the interaction between B7 and CD28, with the aim of rendering cells anergic that would otherwise respond to de novo alloantigens. One such agent, belatacept a fusion protein that specifically blocks the co-stimulatory CD28–B7 interaction has elevated the profile of memory T cells in transplant immunotherapeutics, as memory T cells from prior antigen exposure that no longer require co-stimulation might cross-react with alloantigens .
***Allograft rejection:
Alloreactive memory T cells Effector and memory T cells downregulate CD28 and upregulate the expression of adhesion molecules; however, the precise triggers that induce these differentiation pathways remain incompletely defined. Regardless, co-stimulation promotes the differentiation of naive T cells into memory T cells. The lack of requirement for further co-stimulation combined with the increased expression of adhesion molecules enables these cells to quickly activate and infiltrate inflamed tissues in the periphery to exert their effector function after re-encountering the same antigen. By their very nature, however, effector memory T cells are potent mediators of rejection their low threshold requirement for activation and high levels of adhesion molecules facilitate access to the transplanted tissue and clinical observations have revealed that increased levels of donor-specific, cytokine-producing memory T cells correlate with high instances of rejection and poor long-term allograft survival.
Indeed, effector cells that express low levels of CD28 have been implicated in CD28–B7
co stimulation-blockade-resistant allograft rejection .Other subsets of CD28− T cells that also express high levels of CD2, LFA-1 and VLA-4, are associated with rejection mediated by resistance to belatacept in human studies. These data indicate that co-stimulation blockade, although effective at inhibiting responses to de novo alloantigens, is inadequate at inhibiting pre-existing allospecific memory T-cell responses.
References:
1. Jameson SC, Masopust D. Diversity in T cell memory: an embarrassment of riches. Immunity. 2009;31:859–871.
2. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–712.
3. Lakkis FG, Arakelov A, Konieczny BT, Inoue Y. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6:686–688.
4. Curtsinger JM, Lins DC, Mescher MF. CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C) to TCR/CD8 signaling in response to antigen. J Immunol. 1998;160:3236–3243.
5. Wherry EJ. T cell exhaustion. Nat Immunol.
2011;12:492–499.
Thankyou Amal for you avidity to supply more and more information, two of your phrases are quite informative:they are existing antigen EXPERIENCED cells . Costimulation – blokade(Belatacept) resistant allograft rejection. Donor SPECIFIC cytokine producing Tcells. welldone
Memory cells:
Immunological Memory:
The Role of Memory cells in Transplantation:
Strategies attempted to suppress the effect of memory cells:
Thankyou Assafi you are another very organised writer just a few comments
good that you mentioned they are also B andNK cells because this ca be reflected on site of drug management.
Adonor- specific second set confirms the cross reactivity with similar antigens as he is exposed once to a LD or DD.
Can you ditrctly measure the FREQUENCY of memory cells
But really thankyou
Memory T cells, and their ability to generate an anamnestic response, are vital to protective immunity. Their altered expression of CD28 and adhesion molecules not only explains their physiologic value, but also provides insight into their potentially detrimental impact on allograft survival.
Allospecific memory can be generated through heterologous cross-reactivity and homeostatic proliferation, as well as through prior exposure to allogeneic antigens.
Exposure to previous transplantation,pregnancy and blood transfusion all can promote activation and proliferation of memory cell.
Co-stimulation
Naive T cells require numerous signals to enter a program of differentiation.Following differentiation, the expression of CD28 is markedly downregulated and the resulting memory T cells no longer require co-stimulation for secondary immune responses.
Thus, the lack of CD28 expression is an important hallmark of an antigen-experienced cell in humans and non-human primates 1.
effector memory T cells are potent mediators of rejection — their low threshold requirement for activation and high levels of adhesion molecules facilitate access to the transplanted tissue 2.
effector cells that express low levels of CD28 have been implicated in CD28–B7 co-stimulation-blockade-resistant allograft rejection 3.
Targeting alloreactive memory cells
Cell depletion
Studies of alemtuzumab-mediated depletion in combination with belatacept and sirolimus (which inhibits IL-2 production) have shown that the burst of homeostatic activation is countered by a corresponding burst of TREG and BREG cell generation, and that this phenomenon is associated with exceptionally low rates of rejection 4.
Inhibitors of calcineurin and mammalian target of rapamycin effectively, but non-specifically, impede memory T-cell responses
Co-stimulation blockade inhibits T-cell responses to de novo alloantigen, but does not inhibit allospecific memory T-cell responses
Belatacept( CTLA4-Ig) is a fusion protein that blocks CD28, despite its benefit to improve graft survival compared to calcinurin inhibitors, yet, it increases acute cellular ejection because memory T cells are more resistant to it.
Several therapeutic agents that target molecules upregulated on memory T cells have been shown to synergize with co-stimulation blockade to mitigate the effects of memory T cells in organ transplantation
In case of the patient desires third transplantation the despite negative crossmatch , the patient is sensetized by previous transplantation and require induction with ATG
the presence of memory cells
With other antibodies such as minor HLA And DSA that are not detected require strong immunosuppression with triple therapy steroids ,tacrolimus and MMF
Reference
1 Mou D, Espinosa J, Lo DJ, Kirk AD. CD28 negative T cells: is their loss our gain? Am J Transplant. 2014;14:2460–2466.
2 Krummey SM, Ford ML. Heterogeneity within T cell memory: implications for transplant tolerance. Front Immunol. 2012;3:36.
3 Mou D, Espinosa JE, Stempora L, Iwakoshi NN, Kirk AD. Viral-induced CD28 loss evokes costimulation independent alloimmunity. J Surg Res. 2015;196:241–246.
4 Xu H, et al. Postdepletional lymphocyte reconstitution during belatacept and rapamycin treatment in kidney transplant recipients. Am J Transplant. 2015.
welldone Sherine your plan shows that you understand where aech drug intervenes
Memory T cells ( Antigen-experienced T cells): they are T cells that give long term protective immunity , they are useful in protecting against recurrent infections but they are barrier to successful transplantation and tolerance induction
they are generated by three mechanisms
first one due to sensitization by prior blood transfusion, pregnancy or previous transplantation
second :homeostatic proliferation in cases of lymphopenia due to induction therapy
third :heterologous immunity and cross reactivity.
they lead to acute and chronic rejection.
the frequency of memory T cells in the peripheral blood of renal transplant patients prior to transplant correlates with the risk of developing acute rejection episodes and with poor renal allograft function at 1 year.
Strategies to suppress their effects
· Lymphoablation :
· direct which affect T cell survival and homeostasis by regulation of metabolic pathway of these cells
Alefacept : anti LFA-3 ( molecule detected in T cells) causing depletion of T cells
· Targeting the proliferation of memory cells induced by cytokines and TCR signaling by using JAK inhibitors
· Limiting trafficking of Alloreactive T cells
Reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) have been demonstrated to prolong allograft survival in experimental transplantation .
· · Costimulatory Blockade
· CD28/B7 blockade , ICOS/B7RP-1, CD134/CD134L, CD70/CD27 blockade: improved allograft survival even in donor-sensitized recipients
References
Benichou G , Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol. 2017;8:170.
Su, C.A., Fairchild, R.L. Memory T Cells in Transplantation. Curr Transpl Rep .2014,1: 137–146.
Kitchens WH, Larsen CP, Ford ML. Integrin antagonists for transplant immunosuppression: panacea or peril? Immunotherapy (2011) 3(3):305–7.
Lo DJ, Weaver TA, Stempora L, Mehta AK, Ford ML, Larsen CP, et al. Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression. Am J Transplant (2011) 11(1):22–33.
Valujskikh A. The challenge of inhibiting alloreactive T-cell memory. Am J Transplant (2006) 6(4):647–51.
Blattman JN, Antia R, Sourdive DJ, Wang X, Kaech SM, Murali-Krishna K, et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med. 2002;195:657–64.
Thankyou ALia for mentioning that a previous heameostatic lymphocyte depletion can be a cause of memory cell proliferation
also stratifying your plan of action.
Memory T cells ( Antigen-experienced T cells): they are T cells that give long term protective immunity , they are useful in protecting against recurrent infections but they are barrier to successful transplantation and tolerance induction
they are generated by three mechanisms
first one due to sensitization by prior blood transfusion, pregnancy or previous transplantation
second :homeostatic proliferation in cases of lymphopenia due to induction therapy
third :heterologous immunity and cross reactivity.
they lead to acute and chronic rejection.
the frequency of memory T cells in the peripheral blood of renal transplant patients prior to transplant correlates with the risk of developing acute rejection episodes and with poor renal allograft function at 1 year.
Previous transplantation means sensitisation but although patient is sensitized but once cross match is negative he can proceed to transplant without desensitization
This patient is definitely sensitized but need no sensitisation
the role played by the memory cells in transplantation
Naive t cell recognize alloantigen on the surface of the graft after 3 signal of stimulation then transformed into effector t cell in the 2ry lymphoid organs like lymph nodes and stimulate other t cells plus B cells which finally end with lymphocytes infiltrations (undercontrol of cytokines and chemokines) of the graft and formation of plasma cells and antibodies.
Memory t cells are different in multiple aspect than naive t cells like
1)It has lower threshold of stimulation
2)it can differentiate into effector t cell outside 2 lymphoid organs
3)more infiltrations power to the graft tissue
4)it needs just 2signals for stimulation and bypass signal 2 and drugs blocking it
5)it secrets much abundant cytokines and chemokines leading to more injury
6) it resistant to regulatory tcells and tolerance
the strategies attempted to suppress their effect.
The only available drug in the market which affect it is ATG although it induce lymphopenia which trigger alloreactive Tmemory cells formation.
the strategies attempted to suppress their effect on animal model
1)blocking of infiltration (block chemokines…anti-LFA-1 agent (Efalizumab) but associated with increase risk of malignancy.
2)suppression of proliferation(block cytokines)…Tofacitinib (CP-690550), a JAK-3 inhibitor but associated with sever inhibition of immune system.
3)Blocking the other costimulatory pathways for memory T cells…..4-1BB and OX40/OX40L costimulatory pathway blockade
4)Blocking b cell activation factor (BAFF) by anti-CD154 monoclonal antibody
Finally about the patient who need to do 3rd transplantation
In all types of crossmatch we only take plasma of recipient which contains only antibodies.
We only evaluating his humoral immunity
But we don’t evaluation his cellular immune response
There is what’s called biological basis for immune monitoring assay like cell madiated lympholysis and t cell frequency analysis to assess cellular immune response but till now it only used on research basis and not used for clinical practice.
My center experience
We used to avoid donors with similar antigenic phenotyping to those who already rejected in previous transplantation
And to some extent we prefered to avoid similarities between donor and husband of female recipient even in with negative DSA to his HLA typing.
Reference
Handbook for kidney transplantation by G.danovitch
Thankyou Ramy for your quick but rather general grasp of the subject though not in all points as an example
-relation with T,Bregs.
you have a good plan as regards choosing your donor but the paucity of the latter would you refuse aphenotypically similar donor you get this situation with a second sibling .
It is a wife R versus aD husband for mHLA.
A long-lived immune cell that has the ability to recognize a foreign particle that it previously encountered and consequently mount a faster and stronger immune response
Supplement
Memory cells are long-lived immune cells capable of recognizing foreign particles they were previously exposed to (thus, the memory in their name). These immune cells do not respond immediately when it first encounters an antigen but facilitates a more rapid secondary response when the antigen is encountered on a subsequent occasion.
Examples of memory cells are memory B cells and memory T cells. Memory B cells are clones of a parent B cell that previously served as an antigen-presenting cell and then activated by a helper T cell to proliferate. As clones, the memory B cells bear the same B cell receptors as those of the parent B cell. Therefore, they would be able to detect the same antigen when re-exposed. Memory B cells produce more robust antibody-mediated immune response during re-infection.
Memory T cells are T lymphocytes that have the similar capability of recognizing foreign particles that they previously encountered. But unlike memory B cells, the memory T cells do not produce antibodies. Re-exposure to the pathogens causes them to clone themselves immediately and as such respond to the infection more strongly.
During immune response the effector lymphocytes are activated, but most of these cells are undergo organized death by apoptosis. the survived cells will be the memory cells.
Memory cells have longer lifespan, higher frequency, wider migration pattern, and low threshold fro activation. the response of memory cells is partially dependent on traditional co stimulatory response e.g. B7-CD28 ( so it resistant to inhibition by CTLA4-Ig). these features have significant protective action against infection but dangerous effect on transplanted organs if memory cells are reactive.
CD4 T cells are effector cells during reactivation & provide help in activation of donor reactive effector CD8 T cells. These CD8 T cells are the major force causing allograft rejection. So CD* T cells depletion significantly improve graft survival.
Available immunosuppressant drugs which are effective in inhibition of native T cells but have very little effects on inhibition of memory cells. Alefacept deplete memory cells & spare other sets of T cells. Pretransplant combination of alefacept & CLTA4-Ig tend to be targeting costimulation blocked-resistant CD8 CD2 CD28 effector/memory T cells.
References:
Memory cells are responsible for faster and stronger immune response when they recognize a previously exposed antigens.
Immunological memory is characteristic of immune system by which it can save the stimulus information and give stronger and more rapid response than the first one when it exposed to the same stimulus for the second time even if it occurs after many years .
This is play major role as defence mechanism against different pathogens, in vaccin therapy and also in autoimmune diseases.
Previous transplantation, pregnancy and blood transfusion all contribute in the activation of memory cells causing both acute rejection attacks and / or chronic graft injury.
Regarding the above question I will consider him as sensitized pateint need desensitization protocol then induction by ATG and continue on maintenance dose immunosuppression tacrolimus MMF and steroid.
Dear All
Please answer my question below. It addresses the role of memory cells.
Since memory cells are resistant to immunosuppression, how would you immunosuppress this patient.
“a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative.
Will you considered him sensitised?
how would you immunosuppress this patient?
As this is the third transplantation, it is considered to be a high risk pt, although he had normal DSA, and although he had negative crossmatch . That’s way he will need to be treated as high risk protocol (ATG induction, mmf 2-3 gm, tarolimus)
Dear Dr Ahmed,
As mentioned by my colleagues, this patient is considered sensitized (despite the current negative crossmatch) due to the history of failed 2 kidney allografts. He is likely to have memory cells that are ready to reactivate and attack the new allograft once they are stimulated.
My plan of management (as I will consider the immune suppressant as one line of management of high-risk recipients):
· Induction with a lymphocyte depleting agent (ATG).
· Triple maintenance immune suppressant (Tacrolimus, MMF and steroids).
· I will avoid maintenance immune suppressant minimization protocols.
· Close monitoring of DSA with a low threshold for allograft biopsy whenever DSA titre is rising.
· Early initiation of treatment of rejection whenever there are histological changes suggestive of rejection (even if C4d is negative).
He still sensitized because previous 2 transplantation with development of memory T cells due to clonal proliferation of primary effector T cells
immunosupressed by
induction for lymphocyte depletion by ATG or basiliximab
then triple therapy by Tacrolimus,MMF, steroids
Being with history of 2 previous kidney transplant make him highly sensitized.
Mostly will have a sensitized memory cells which may adversely endanger his third graft and causes all types of rejection and reduces graft survival.
Transplantation can be attempted with a protocol for highly sensitized patient, flow cytometry & CDC to be carried out.less can be done regarding T cell sensitization and risk of rejection. ATG ,Anti CD20 or other desensitization method can be used although mostly work with ABMR.
This gentleman has been considered sensitized as he had previous 2 transplants that can be considered high immunological risk. Previous transplantation will result in the development of memory T cells and increase risk for rejection and graft failure. Regarding transplanting another kidney will be challenging but can be done with high risk protocol including and induction with ATG and costimulatory blockade. maintenance according to elite – symphony trial. vigilant monitoring must be done to avoid rejection.
yes he is sensitized from previous two transplant despite his currnet croosmatch negative and no DSA but he had T and B memory cells and with in time post transplant he can perform DSAs agianst HLA antigesn for both class1 , 11 , so he should recevied induction immuntherapy as high immunological risk with close monitoring by DSAs level
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
Although this gentleman has a negative crossmatch and his DSA is currently negative. He is considered sensitized as he had previous 2 transplants that can result in the development of memory T cells which can increase his risk for rejection. However, he can be transplanted with with high risk protocol including and induction with ATG and maintenance on triple immunosuppression(Tacrolimus with high trough level 8-10 ng/ml, MMF 2-3 gm, steroids).He will need close monitoring of his DSA and perhaps a protocol biopsy
Agree, well done
Memory T cells are the hall mark of the adaptive immune system that play a protective role against invading pathogens.
In transplantation they are both friends and foes; they are needed in the defense against invading pathogens, so their absence or inhibition would expose transplant patients to infections. However in transplantation, a significant proportion of memory T cells, either pre-existing or de novo generated, can directly attack transplants ,threatens transplant survival and render patients resistant to tolerance .
Memory T cells possess unique features compared to naive T cells being long-lived cells which can replenish themselves, much lower activation threshold, not confined to lymphoid tissue so readily accessible to antigens.
There are 3 independent mechanisms for the generation of allo-reactive memory T cells:
§ Antigen sensitization is the main source of memory T cells including blood transfusion, pregnancy or prior transplant
§ During homeostatic proliferation, this occurs in response to transient lymphopenia and induces the proliferation and differentiation of naive T cells into memory cells; so often seen after T-cell depletion therapy
§ In response to unrelated infectious or environmental antigens that can cross-react with donor allogeneic MHC molecules creating a situation known as heterologous immunity
Memory CD4+ T cells, upon reactivation, give rise to effector CD4+ T cells which in turn activate CD8+ T cells leading to graft rejection
While Naive T cell responses are adequately controlled with immunosuppressive drugs, memory t cells don’t respond to such therapies , and promote formation of DSAs with subsequent ABMR
Strategies attempted to suppress the effects of Memory T cells include:
Lympho-ablation
Induction therapy is widely used in clinical transplantation
ATG (polyclonal) or Anti CD52 – Alemtuzumab (monoclonal AB) are most commonly used in sensitized patients
Although ATG induced lymphopenia Triger generation of alloreactive memory T cells, but it was found that ATG significantly increase T regulatory cells which suppress memory T cells, So better survival of graft was obtained by ATG induction
Despite memory T cells are the targets, they are still less susceptible than naive T cells and a portion can still survive after induction therapy and can be responsible for acute graft rejection .
Alefacept, Anti CD2 ,which is expressed on memory T cells , selectively depletes memory cells and shows promising results
Co-stimulatory Blockade
Belatacept( CTLA4-Ig) is a fusion protein that blocks CD28, despite its benefit to improve graft survival compared to calcinurin inhibitors, yet, it increases acute cellular ejection because memory T cells are more resistant to it.
Metabolic pathway
manipulating T cell survival & homeostasis by regulating cell metabolic pathways as immune cells use different mechanism for energy production
limiting trafficking of allo-reactive memory T cells
MEMORY T CELLS IN TRANSPLANTATION—PROGRESS AND CHALLENGES. . Xian C. Li, Malgosia Kloc, and Rafik M. Ghobrial. Curr Opin Organ Transplant. 2013 Aug; 18(4): 387–392.
Role of Memory T Cells in Allograft Rejection and Tolerance. Gilles Benichou, Bruno Gonzalez, Jose Marino, Katayoun Ayasoufi, and Anna Valujskikh. Front Immunol. 2017; 8: 170.
Role of memory T cells and perspectives for intervention in organ transplantation. Kailin Lin,Song Chen,and Gang Chen. Front. Immunol., 14 September 2015
Thanks Dr Ahmed for your replies
Looks you have not read your colleagues’ replies. Memory cells are resistant to many immunosuppressive medications notably co-stimulatory blockade and also depleting agents.
Please review your reply and answer my question posted above
Memory cells themselves are not the problem but the more important is their specificity to certain alloantigens. Lymphocyte depletion eliminates allospecific T cells but spares memory cells. the cross-reaction is a problem in humans. this was not well studied in mice because they don’t have a chance to be sensitized like humans. humans may be sensitized due to previous infection, blood transfusion, or even natural pregnancy. calcineurin inhibitors are good for suppression but high doses will be at the expense of risk of infection.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341793/
The problem with the scenario of third transplantation I think is not only memory cells but the risk of other antibodies that may be not detected as DSA.
Excellent Mahmud
You made a very consisted and up to the point. Well done
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitized?
Yes, he is still sensitized. DSA reflects B cell memory, but he can still have Memory T cells generated in response to previous transplantation.
Memory cells are heterogeneous, including multiple cell types (T cells, B cells, NK cells, macrophages, etc.), and even within each cell type, there are also many different subsets. They are progenies of naïve lymphocytes and developed after productive responses upon antigen stimulation. Memory T cells have clear survival advantages over their naïve counterparts, and they are often resistant to lymphocyte-depleting therapies.
Memory T cells generated in response to one antigen can react to other unrelated antigens, a process called heterologous immunity. A major implication of heterologous immunity in transplantation is that pathogen-specific memory T cells, can respond to alloantigens, and therefore they are alloreactive, which can mediate allograft rejection. Patients with a higher frequency of memory T cells are associated with worse transplant outcomes under conventional immunosuppression.
Current immunosuppressive drugs that are effective at inhibiting naïve T cells have minimal effects at preventing memory T cell-mediated rejection. In fact, there is a strong correlation between the presence of pre-transplant alloreactive memory T cells and acute rejection episodes that occurred despite tacrolimus- and sirolimus-based therapies. Moreover, depletion therapies (e.g., anti-thymocyte globulin or ATG) are less effective at eliminating pre-existing memory T cells. In truth, following depletion therapies, memory CD4+ T cells are a dominant cell type remaining and are capable of initiating rejection episodes. Clearly, alternative approaches are needed to target alloreactive memory T cells in transplant settings.
There have been other attempts to control memory T cells in transplant models, however, all are still experimental, such as the NF-κB blocker LF15-0195, an analog of 15-deoxyspergualin, prevented activation of donor-specific memory CD8 T cells and synergized with costimulatory blockade to induce heart allograft survival in donor skin-pre-sensitized mice.
Regarding B cell memory in transplantation, advances in detecting DSA facilitate the identification of donor-antigen sensitized candidates, to whom transplantation may not be considered an option or appropriate desensitization protocols need to be applied. Patients with complement C1q-binding DSAs after kidney transplantation exhibit the lowest 5-year rate of graft survival, as compared with patients with non-complement-binding DSAs or without detectable DSAs. Eculizumab can significantly decrease the incidence of AMR in kidney recipients who had a positive crossmatch against their living donor.
References:
Chen W, Ghobrial RM, Li XC. The Evolving Roles of Memory Immune Cells in Transplantation. Transplantation. 2015 Oct;99(10):2029-37.
Please reply to my question posted above
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
Although this patient’s cross matching test is negative and there is no DSA but he had underwent a previous sensitizing events( 2 kidney transplantation) so he considered a sensitized patient. No desensitization is required given his current testing results, induction with ATG and maintenance therapy consist of Tac,MMF & gradually tapered steroid with monitoring of DSA level post transplant and /or protocol biopsy.
Excellent, there is the role of memory cells
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
This patient has history of exposure to foreign MHCs due to prior transplants. So, although DSAs are absent, he is still a sensitized patient. No desensitization is required as DSA are negative, but patient will require Induction with ATG, Tac/MMF/steroids as immunosuppression and monitoring for DSAs in post-transplant period.
Memory cells: Memory T cells are formed either by direct exposure to MHCs during a sensitization event like pregnancy, blood transfusion or prior transplant or by exposure to peptides of commensal bacteria or environmental antigens mimicking molecular structure of alloantigens. (1)
These are different from naive T cells. They have increased expression of adhesion molecules and decreased need for co-stimulation, causing resistance to conventional immunosuppression and co-stimulation blockade, leading to an important role in graft rejection. (2,3)
Memory CD4+ T cells, upon reactivation, give rise to effector CD4+ T cells which in turn activate CD8+ T cells leading to graft rejection. (4)
Strategies attempted to suppress the effects of Memory T cells include:
a) Lymphoablation: Antibody for lymphocyte depletion (like anti thymocyte globulin, anti CD52 monoclonal antibody) are the most commonly used induction therapy in sensitized patients. Even though the target is memory T cells, they are still less susceptible than naive T cells and a portion of them survive and these depletion-resistant memory T cells are responsible for acute graft rejection in kidney transplant recipients. (5) Alefacept is a fusion protein which targets memory/effector T cells which is shown to be responsible for improved graft survival by depleting effector memory cells resistant to costimulatory blockade in nonhuman primates. (6) Siplizumab, humanized BTI-322 has been used as a part of tolerance inducing protocol with successful management of HLA mismatched kidney transplant recipients without maintenance immunosuppression. (7)
b) T cell costimulation blockade: Belatacept/ CTLA4 Ig, a fusion protein blocks CD28, has been shown to improve graft survival rates but has increased acute cellular ejection as memory T cells are more resistant to it. Other co-stimulation blocking molecules include anti CD40/CD154 and anti LAG-3/CD223. (1)
c) Manipulating metabolic pathways: Calcineurin inhibition and mTOR signal inhibition affect differentiation and activation of memory T cells. (2) AMP activated protein kinase inhibition and aquaporin 4 inhibition are the strategies in focus for further research to suppress memory T cells. (1)
References:
1) Nicosia M, Fairchild RL, Valujskikh A. Memory T cells in transplantation: old challenges define new directions. Transplantation 202;104:2024-2034.
2) Espinosa JR, Samy KP, Kirk AD. Memory T cells in organ transplantation: progress and challenges. Nat Rev Nephrol 2016;12:339-347
3) Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant frequency of donor specific, IFN-gamma producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J Immunol 1999;163:2267-2275.
4) Benichou G, Gonzalez B, Marino J, et al. Role of memory T cells in allograft rejection and tolerance. Front Immunol 2017;8:170.
5) Pearl JP, Parris J, Hale DA, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T cell depletion. Am J Transplant 2005;5:465-474.
6) Weaver TA, Charafeddine AH, Agarwal A, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med 2009;15:746-749.
7) Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Eng J Med 2008;358:353-361.
Excellent Amit
I will quote this from your replies” T cell co-stimulation blockade: Belatacept/ CTLA4 Ig, a fusion protein blocks CD28, has been shown to improve graft survival rates but has increased acute cellular ejection as memory T cells are more resistant to it.”
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
I assume he is DSA negative, so he is not sensitised.
Thanks Dr Mahmoud
He is definitely sensitised and the memory cells play an important role here. Read the replies above
As DSA & crosshatch both negative we can not consider him a sensitized patient but he may have activated memory cells & 221 mismatched so he had high risk for graft rejection & need close & regular monitoring of DSA.
The clinical question here addressed by this real-life scenario:
a 53-year-old CKD patient who had 2 failed grafts is interested to have his third kidney. He has no DSA. He received a kidney offer 221 mismatch. His crossmatch is negative. Will you considered him sensitised?
Negative cross match and no DSAs can’t rule out presence of memory T cells ( that have been generated from transplantation twice)
Yet he needs no sensitization ( as there is no DSAs to remove )
Yes, sensitised and the memory cells plays an important role in mounting immune response
Memory cell have immune responce more strong than native T cell.
Memory cell have recall response resistant to inhibition by CTL A4 Ig [ Belatacept].
So it has deleterious effect to transplant organ
Memary cell generated for 3 reasons.
1- in responce to Vaccinatione or
Infection
2-Blood transfusion, privous organ Transplantation, pregnancy
3-after recovery from lymphopenia (after AT G induction Therapy)
patients with high level of memory cell have higher incidence of acute rejection and also in patient receive Belatacept experience Sever rejection episodes Than patients on tacrolimus because belatacept dose not inhibit Т-сell memory activation
memory cell poorly controlled by conventional immune suppressive Therapy and cause irreversible Cellular and or Humoral allograft rejection
using maintenance regimens including CNI seem to do best in alemtuzumab-based maintenance reduction strategies
Alefacept is Human Fusion protein of CD2 ligand with IgG1 shown to inhibit T-cell proliferation in combination with belatacept-based maintenance Therapy.
Reference
1. Danovithch G. Hand book of Kidney Transplantation , 6th ed.
2-Kidney Transplantation Principles and Practice. EIGHTH EDITION
Memory T cells are responsible for more rapid and intense immune response on re exposure to antigens ,
This is beneficial in cases of infections , malignancies ,But in the context of renal transplantation, the memory T cells have determintal effects on graft outcome
memory cells generated by previous donor antigen sensitization through blood transfusion, previous transplant, pregnancy, or through cross-reactive heterologous immunity contribute to both acute rejection episodes and the development of chronic graft injury
Subtypes of memory cells include
Central memory cells
Effector memory cells
Tissue resident memory cells
Follicular helper memory
During differentiation of memory T cells , the T cell receptor and the co stimulatory signals, are adjusted to ensure more rapid with higher magnitude immune response , and this explains why memory cells respond to lower antigen doses or those who are presented imperfectly by APCs
Activation of memory CD4 cells causes Activation of CD8 cells which is the main drive for allograft rejection
While Denovo T cell responses are adequately controlled with immunosuppressive drugs, memory t cells don’t respond to such therapies , and promote formation of DSAs with subsequent ABMR
Their role after transplantation:
1.CD4 cells secreting INF gamma , facilitate DSA formation
2. Early contact to CD8 memory cells , leads to upregulation of adhesive molecules and chemokines facilitating entry of recepient leucocytes to the graft
3.once inside the graft , memory CD8 cells proliferate extensively
4. Presence of memory T cells render patients resistant to tolerance
Strategies for memory cells suppression :
1.lymphoablation
With induction monoclonal Abs being the most common way
Memory cells are less responsive to monoclonal TCell depletion than naive T cells
CD4 memory cells are more resistant that 8 ,for depletion with monoclonal Abs
Alefacept, Anti CD2 ,which is expressed on memory T cells , selectively deplets memory cells and shows promising results
FTY720, a sphingosine-1 phosphate receptor agonist, inhibit lymphocyte migration from the thymus and peripheral lymphoid tissues, inhibiting them from trafficking to peripheral graft sites.
Some studies have a shown that disruption of adhesion molecules (( leukocyte integrins such as LFA-1 and VLA-4)) is quite effective in inhibiting memory T cell infiltration into grafts.
memory CD4+ and CD8+ T cells in humans (Temra) lose CD28 expression and become insensitive to the lack of co stimulatory blocking
some studies have proposed that memory T cells uses alternative co-stimulatory pathways for activation .
For CD8+ T cells, the engagement of 4-1BB (CD137) by its ligand has been shown to provide both CD28-dependent and CD28-independent signals that result in proliferation, cytokine production, augmented cytotoxic effector activity, and enhanced cell survival
Blockade of the 4-1BB co-stimulatory pathway in mouse models has shown some efficacy in enhansing survival of allografts
Another co stimulatory pathway that could be targeted , especially for CD4 t helper cells
, is the OX40/OX40L pathway.
Blocking this pathway has been shown to reduce memory CD4+ T cell formation.
Cho HR, Kwon B, Yagita H, La S, Lee EA, Kim JE, et al. Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival. Transpl Int. 2004;17:351–61.
Salek-Ardakani S, Song J, Halteman BS, Jember AG, Akiba H, Yagita H, et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J Exp Med. 2003;198:315–24.
Selin LK, Cornberg M, Brehm MA, Kim SK, Calcagno C, Ghersi D, et al. CD8 memory T cells: cross-reactivity and heterologous immunity. Semin Immunol. 2004;16:335–47.
Zhang Q, Chen Y, Fairchild RL, Heeger PS, Valujskikh A. Lymphoid sequestration of alloreactive memory CD4 T cells promotes cardiac allograft survival. J Immunol. 2006;176:770–7.
Memory T cells have many characters that may threaten the graft survival in organ transplantation:
1/ Memory T cells have low stimulation threshold.
2/ Memory T cells are resistant to costimulation blocking therapies.
3/ Memory T cells can be produced by transient lymphopenia in a process called homeostatic proliferation and in transplantation sever lymphopenia may occur as a result of the use of T cell depleting therapies.
4/ Memory T cells that are produced in response to infection or environmental antigens can cross react with donor HLA antigens.
Many strategies and experimental studies have shown that the effect of memory T cells on the graft may be decreased through prevention of their infiltration of the graft , inhibition of their proliferation, prevention of their activation , and also by their depletion.
The challenge is that controlling the effect of memory T cells on the allograft through these mechanisms should not influence the risk of infection and malignancy to the host.
however, recent studies proved that recalling response of memory T cell in case of infection and allograft is different,
Ref:
Frontiers | Role of Memory T Cells and Perspectives for Intervention in Organ Transplantation | Immunology (frontiersin.org)
Memory cells are generated by
– identification of peptides from commensal bacteria or environmental antigens presented by self-MHC, similar to complexes formed by allogeneic MHC molecules bound to other peptides.
-through homeostatic proliferation in a lymphopenic environment,as potentially alloreactive and pathogenic T cells ,this can impair tolerance induction to allografts .
-Prolonged exposure to dialysis increases the risk of evolving of alloreactive memory T cells . (1)
-Sawinski et al. stated that low serum levels of 25-OH-vitamin D in dialysis patients is directly proportionate with the frequency of alloreactive memory T cells independently.(2)
Donor-reactive memory T cells can lead to allograft rejection inspite of interruption of essential costimulatory pathways, CD28/CD80/CD86 and CD40/CD154.
Memory CD4+ T cells act as effector cells upon reactivation, and help in the activation of donor-reactive effector CD8+ T cells which are the ignition behind allograft rejection ,that is why CD8+ T cell depletion or limiting their trafficking into the graft extends allograft survival .
Memory CD4+ T cells can be resistant to immunosuppresion and can provide help for the generation of DSA leading to alloantibody-mediated graft injury as well (1)
Studies noticed therapeutic targets to control CD40-independent DSA generation by memory CD4+ T cells:
– gamma interferon (IFNγ) secretion by memory helper T cells is essential for de novo DSA generation .
– CD40- independent helper functions of donor-reactive memory CD4+ T cells were inhibited by B cell activating factor and a proliferation-inducing ligand, cytokines critical for B cell survival.(3)
Endogenous memory CD8+ T cells react to donor MHC class I molecules and infiltrate allografts within hours after reperfusion,these memory CD8+ T cells proliferate and upregulate the expression of ICOS, and secrete IFNγ in ICOS-dependent manner . Increasing graft cold ischemia storage time enhanced effector functions of endogenous memory CD8+ T cells enabling them to promptly reject a allograft despite costimulatory blockage.(4)
Although memory T cells are pathogenic in transplantation, in other situations they established regulatory capacity and suppress pro-inflammatory immune responses, indicating that lymphoablative methods against memory T cells can interfere with allograft acceptance and tolerance(5)
Strategies attempted to supress their effects
-lymphoablation
Decreasing CD4+ T helper signals during lymphoablation increases the efficacy of mATG in limiting memory T cell expansion and extends allograft survival in sensitized patients.
Ale fatacept targeting effector memory T cells.
– Costimulatory Blockade
Belatacept, a second generation of CTLA4-Ig, prevents allograft rejection and minimize the toxic side effects of calcineurin inhibitors on the other hand it has higher rates of acute rejection compared to CNI treatment.
The sensitivity of memory T cells to immunosuppression is dependent on their origin
– Limiting Trafficking of Memory T Cells
Reagents blocking LFA-1 (leukocyte function-associated antigen-1, an αLβ2 integrin) and VLA-4 (very late antigen-4, an α4β1 integrin) have shown to prolong allograft survival.(1)
1-Benichou G, Gonzalez B, Marino J, Ayasoufi K and Valujskikh A (2017) Role of Memory T Cells in Allograft Rejection and Tolerance. Front. Immunol. 8:170
2-Sawinski D, Uribarri J, Peace D, Yao T, Wauhop P, Trzcinka P, et al. 25-OH-vitamin D deficiency and cellular alloimmunity as measured by panel of reactive T cell testing in dialysis patients. Am J Transplant (2010) 10(10):2287–95.
3-Gorbacheva V, Ayasoufi K, Fan R, Baldwin WM III, Valujskikh A. B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. Am J Transplant (2015) 15(2):346–57.
4-Li XL, Menoret S, Bezie S, Caron L, Chabannes D, Hill M, et al. Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance. J Immunol (2010) 185(2):823–33.
5- Krupnick AS, Lin X, Li W, Higashikubo R, Zinselmeyer BH, Hartzler H, et al. Central memory CD8+ T lymphocytes mediate lung allograft acceptance. J Clin Invest (2014) 124(3):1130–43.
Thanks Doaa
See my answers above
Memory cells function and production:
Antigen-experienced T cells, also known as memory T cells, are functionally and
phenotypically distinct from naive T.Tell (1). It does not require costimulation lead to its
early response.
Memory T cells from decayed effectors T and B cells.
It has long life and strong immunolocal response with minimum triggering factors.
Also it respond both to previous exposed antigen and cross react with nonidentical
antigen, this enhance it respond and hinder effective allograft transplantation by this
alloimmunity.
T cell produced by sequential and parallel process, which needs interleukin for
stimulation and tracking to different type of memory t cell i.e. effector memory cells and
central memory cells. (3)
Costimulation:
Process needed for activation of naïve t cell it depends on interaction between B7
protein on antigen-presenting cells (APCs) and CD28 (also known as cytotoxic T-
lymphocyte-associated protein. On it, based the therapeutic agents designed to block
the interaction between B7 and CD28, Belatacept, a fusion protein that specifically
blocks the co-stimulatory CD28–B7 interaction. (4).
Adhesion molecule expression:
Following T.cell activation and interaction with C28, gains the expression of adhesion
molecules such as CD2, leukocyte function-associated antigen-1 (LFA-1) and very late
antigen-4 (VLA-4).
CD2 aids T-cell activation and adhesion by binding to LFA-3 on APCs and inflamed
tissues.
LFA-1 and VLA-4 bind intercellular adhesion molecule-1 (ICAM-1) and vascular cell
adhesion molecule-1 (VCAM-1), respectively, on activated peripheral vascular
endothelium at sites of inflammation, and are involved in cell migration and extravasation
required for effector functions.(5).
Drug control of memory cells:
Rabbit antithymocyte globulin (rATG), this agent induces profound depletion of T cells
and apoptosis in B-cell subsets.
Alemtuzumab, a monoclonal antibody preparation targeting the cell-surface protein
CD52, is also highly effective at depleting peripheral and secondary lymphoid T and B
cells.
Alefacept inhibit CD2.
Efalizumab inhibit LFA-1.
Natalizumab inhibit VLA-4.
Calcineurin and mTOR inhibit naïve and memory T.cell signaling. During activation and
prevent T.cell responses.
Reference:
1- Jaclyn R. Espinosa,1 Kannan P. Samy et al, Memory T cells in organ transplantation: progress and challenges. Nat Rev Nephrol. 2016 Jun; 12(6): 339–347..
Dear Dr Mohammed
Thank you for your replies. Read your reference carefully. Can you summarise the effect of depleting antibodies on memory cells?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341793/
Antibody for lymphocyte depletion (like anti thymocyte globulin, anti CD52 monoclonal antibody) are the most commonly used induction therapy in sensitized patients. Even though the target is memory T cells, they are still less susceptible than naive T cells and a portion of them survive and these depletion-resistant memory T cells are responsible for acute graft rejection in kidney transplant recipients. Furthermore, residual naive T cells expand resulting in acquisition of functional memory T cells.
Excellent Amit
Well done
Calcineurin inhibitors:
The CNIs ciclosporin A and tacrolimus prevent T-cell proliferation and cytokine production by inhibiting calcineurin and subsequent signalling by nuclear factor of activated T cells, which effectively suppresses TCR-mediated activation regardless of the maturation state of the cell.
mTOR inhibitors
T-cell maturation induces various metabolic alterations that affect the differentiation and activation of these cells; inhibiting the activation of mTOR fundamentally alters this metabolic programming,
.
Blocking differentiation:
The desire for targeted therapeutics has driven the development of numerous monoclonal antibodies and fusion proteins that show a high degree of specificity for molecules relevant to the differentiation of memory T cells. The majority of these agents have not yet been tested in patients.
Co-stimulation blockade
Blockade of co-stimulatory molecules has been a clinical focus in transplant immunosuppression and contributed to the FDA approval of belatacept for use in transplantation in 2011 . Belatacept was developed as a potential replacement for CNIs; its selective targeting of de novo allospecific responses has the advantage of sparing previously acquired protective immunity, but this selectivity has perhaps unveiled the importance of previously under-appreciated allospecific memory. Specifically, treatment with belatacept has proven to be ineffective in a substantial minority of patients, which has presented a hurdle to its clinical use.
Targeting co-stimulation and adhesion molecules
alefacept, targets memory T cells in by inducing their apoptosis, prompting investigation into its potential use in the setting of transplantationThe combined use of alefacept and belatacept in non-human primate models of kidney transplantation resulted in the depletion of CD4+ and CD8+ effector memory T cells and improvement in allograft survival compared to co-stimulation blockade alone.
It is well established nowadays that memory T cells accelerate allograft rejection and prevent transplant tolerance. However, Memory cells constitute a challenge in transplant immunology due to multiple factors:
· Heterogenecity in the phenotype of memory T cells.
· There’s no current information about about the pathogenicity of tissue resident alloreactive T-cells.
· Memory T cells response to immunosuppression depend on their origins meaning that patients with similar T cell memory profile may require different ttt plans .
· Resistance to co-stimulation blockade .
· Depletion therapies inhibit naïve T cells but ineffective in inhibiting memory T cells .
· After depletion therapy, memory CD4 T cells are still there and may start rejection.
Strategies Used to suppress memory cells :
· lympho-ablation
· Manipulating metabolic pathway
· T cell co-stimulation inhibition
· For memory B cells, therapeutic approaches including a combination of targeting memory B cells( anti CD20), Proteasome inhibitors, IVIG + PTx were used but still no definite approach was clarified till now .
Amir AL, D’Orsogna LJ, Roelen DL, van Loenen MM, Hagedoorn RS, de Boer R, et al. Allo-HLA reactivity of virus-specific memory T cells is common. Blood (2010) 115(15):3146–57.10.1182/blood-2009-07-234906 [PubMed] [CrossRef] [Google Scholar]
Pantenburg B, Heinzel F, Das L, Heeger PS, Valujskikh A. T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol (2002) 169(7):3686–93.10.4049/jimmunol.169.7.3686 [PubMed] [CrossRef] [Google Scholar]
Nadazdin O, Boskovic S, Murakami T, O’Connor DH, Wiseman RW, Karl JA, et al. Phenotype, distribution and alloreactive properties of memory T cells from cynomolgus monkeys. Am J Transplant (2010) 10(6):1375–84.10.1111/j.1600-6143.2010.03119.x [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Cho BK, Rao VP, Ge Q, Eisen HN, Chen J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med (2000) 192(4):549–56.10.1084/jem.192.4.549 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
This real-life scenario by Professor Halawa addresses the clinical question here:
A 53-year-old CKD patient who had two failed grafts is interested in having his third kidney. He has no DSA. He received a kidney offer of 221 mismatches. His crossmatch is negative. Will you consider him sensitized?
Before answering this, consider the concepts of serological and cellular memory.
His DSA negative but still have history. Of transplantation which put him at risk for recall memory T.cell sanitization.(Star risk assessment tool)
Excellent
his history put him at risk
but now cross match is negative
so will not consider him sensitized now as he needs no desensitization protocol before transplantation because there is no DSA at that time but will follow closely especially in the early period post transplant, then yearly.
Sensitization refers to a pretransplantation state, where are anti-HLA antibodies circulating in the blood or to the potential for rapid production of HLA antibodies after transplantation through an immune memory response.
Any level of detectable antibody may be considered sensitization as defined the high risk recipients for kidney rejection with PRA more than 0 and any presence of DSA. For the
solid phase assays and flow SAB assay, MFI values of HLA antibodies are semiquantitative
and not equivalent to antibody titers or strength.
So based on this definition the patient is sensitized, and we need to check the HLA typing of previous donors to look in deep the mismatches, and extrapolate the possible
preformed memory cells which could be activate when re-exposed to same HLA
antigens.
In this particular
patient with history of 2 failed grafts, we need to evaluate the causes of
previous failure. if no DSA are detected using solid phase assays, this means the no IgG against donor HLA are not detected. However, IgM could be the culprit as thy are not detected. False negative results could be secondary to previous exposure to IVIG received during previous transplantations as desensitization or treatment for antibody mediated rejection, taking in consideration that he has already to failed grafts.
But the negative crossmatch, excludes the presence of IgM in the recipients serum.
In high risk patients a biopsy is recommended during the first 3 months after transplantation in addition to DSAs level. If DSA are present or if the biopsy shows subclinical rejection, treatment of AMR should be initiated. In the absence of AMR in biopsy, DSA should be monitored and immunosuppression maintained at higher levels.
References:
uptodate
https://doi.org/10.1161/CIR.0000000000000598
What really matter, IgG or IgM in regard to transplant immunology?
Preformed and de novo IgG donor specific HLA antibodies are associated with acute and chronic antibody mediated rejection (AMR) and inferior renal allograft survival. That’s why our approach to identify preformed IgG DSA in the pretransplant period.
However, some patients with AMR have no detectable circulating IgG HLA DSA and it is presumed that these antibodies are either absent or bound to the allograft. IgM HLA antibodies are traditionally thought to be harmless autoantibodies and there are few studies attributing a more pathogenic role for these antibodies in renal transplantation. A group of British researchers studied 24 recipients (17 male, 7 female, mean age 43.7 years), transplanted between 2004-2011, with allograft dysfunction and histological features suggestive of AMR but with no detectable IgG DSA. None of the 24 patients had third party IgG HLA antibodies or DSA prior to transplantation or at the time of indicative biopsy. However, 17/24 (70.8%) screened positive for the presence of IgM HLA antibodies and 12/17 (70.5%) were identified as having Class I IgM DSA. This preliminary study implies that pre-formed IgM antibodies may not be harmless autoantibodies and that the presence of IgM DSA should be sought in patients with IgG HLA- or DSA-negative AMR.
So although, classically we perform solid phase assays to identify the presence IgG DSAs, a negative solid phase assay in the setting of possible antibody mediated rejection, the presence of IgM should be investigated.
The assessment of IgM DSAs levels in cultured PBMCs may be employed as a biomarker of antibody mediated immune response, which may provide an opportunity for early interventions before IgG DSAs production, which may result in AMR development in serum
References
1-Significance of HLA IgM and IgM Donor Specific Antibodies in Renal Transplantation. P. Dodd, M. Willicombe, P. Brookes, C. Roufosse, E. Santos-Nunez, D. Goodall, C. Clarke, R. Charif, J. Galliford, A. McLean, D. Taube. Imperial College Renal and Transplant Centre, London, United Kingdom
2-Impact of Immunoglobulin M-Type Donor-Specific Human Leukocyte Antigen–Antibody Levels in Supernatants from Cultured Peripheral Blood Mononuclear Cells as Predictors of Antibody-Mediated Rejection Ryoichi Imamura , Yoshiko Matsuda ,*, Koichi Tsutahara , Norio Nonomura and Shiro Takahara
Excellent
Yes, IgG is more important. IgM could be damaging.
IgG
IgM doesnot matter
IgM may matter
As mentioned by my colleagues that IgM antibodies are of lower affinity to their antigens than IgG antibodies that arise later.
The switch from IgM to IgG antibodies is referred to as isotype switching and is mediated by T lymphocyte help via the CD40L-CD40 pathway and the action of cytokines (1). These points make the IgG more clinically significant in the field of transplantation as they are persistent, has a higher affinity to target antigens and their titre will rise progressively with the persistent stimulation of the immune response, unlike IgM which will decrease over time (1).
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
Preformed and de novo IgG DSA are associated with acute and chronic antibody mediated rejection and decreased renal allograft survival. in certain circumstances AMR have no detectable circulating IgG HLA DSA. it IgM HLA antibodies are used to thought to be harmless autoantibodies and few studies proved pathogenic role for these antibodies in renal transplantation
Good.
Please consider writing in your own style.
memory cells are originated from naïve lymphocytes after productive response to antigen stimulation so it is different between individuals due to different immune history, pathogen exposure & age
process of memory T cell differentiation after antigen reencountering is rapid and responds to low antigen doses with limited costimulation (antigens presented by non professional antigen presenting cells) (1)
It is essential for host defense against infection but very dangerous in transplantation
Recent studies showed that some innate immune cells as NK cells & macrophages can develop memory properties (2)
memory T cells are long lived & capable of self renewing (3)
memory cells have low activation threshold due to decreased reliance on costimulatory signals for activation (4)
memory cells are challenging in transplant:
patients with higher frequency of alloreactive memory T cells have worse transplant outcome (5)
they are resistant to tolerization (6)
current immunosuppressive drugs, including depletion therapies inhibit naïve T cells but ineffective in inhibiting memory T cells mediated rejection (7)
after depletion therapy, memory CD4 T cells are the remaining cell type & are able to initiate rejection episode (8)
Resistant to costimulation blockade
Costimulation blockade of the CD28 pathway prevent alloantibody formation after transplant but presence of memory T cells resistant to costimulatory blockade increase frequency & severity of acute rejection in patients receiving Belatacept (9)
Targeting alloreactive T cell memory
(1) Jameson SC, Masopust D. Diversity in T cell memory: an embarrassment of riches. Immunity (2009) 31(6):859–71. doi:10.1016/j.immuni.2009.11.007
(2) Liu W, Xiao X, Demirci G, Madsen J, Li XC. Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms. J Immunol. 2012; 188:2703.
(3) Pearl JP, Parris J, Hale DA, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005; 5:465.
(4) Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection. J Immunol. 2006; 176:1394.
(5) Heeger PS, Greenspan NS, Kuhlenschmidt S, et al. Pretransplant Frequency of Donor-Specific, IFN-gamma-Producing Lymphocytes Is a Manifestation of Immunologic Memory and Correlates with the Risk of Posttransplant Rejection Episodes. J Immunol. 1999; 163:2267
(6) Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection. J Immunol. 2006; 176:1394
(7) Page AJ, Ford ML, Kirk AD. Memory T-cell-specific therapeutics in organ transplantation. CurrOpin Organ Transplant. 2009; 14:643
(8) Najafian N, Salama AD, Fedoseyeva EV, Benichou G, Sayegh MH. Enzyme-linked immunosorbent spot assay analysis of peripheral blood lymphocyte reactivity to donor HLA-DR peptides: potential novel assay for prediction of outcomes for renal transplant recipients. J Am Soc Nephrol. 2002;13:252–9
(9) Cortes-Cerisuelo M, Laurie SJ, Mathews DV, Winterberg PD, Larsen CP, Adams AB, et al. Increased pretransplant frequency of CD28 + CD4 + TEM predicts belatacept-resistant rejection in human renal transplant recipients. Am J Transpl. 2017;17(9):2350–62
(10) Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV, et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med (2009) 15(7):746–9.
(11) Priyadharshini B, Turka LA. T-cell energy metabolism as a controller of cell fate in transplantation. Curr Opin Organ Transplant (2015) 20(1):21–8
Excellent response
Review your writing style
Signal 2 with engagement of co-stimulating receptors on T lymphocytes and their ligands on APCs has a crucial role in differentiation and full proliferation of effector lymphocytes. Few effector lymphocytes give rise to memory T lymphocyte. Memory T lymphocytes generate a much stronger immune response (recall response) compared to naïve T lymphocytes (primary response). For some reasons, memory lymphocytes make a formidable barrier, including their recall response, and the ubiquitous presence of them. Higher frequency of memory T cells against donor antigens correlates with higher incidence of acute rejection. Recall response is partially dependent on co-stimulatory pathways such as B7-CD28, so inhibition of these pathways, for example by CTLA4-Ig (Belatacept) does not adequately inhibit activation of memory T cells, and as a result, severe rejection episodes are more frequent with Belatacept than Tacrolimus.
Since activation of the mTOR pathway in an increased number of CD8 T cells in belatacept refractory rejection was described, mTOR inhibitors can be utilized as a rescue therapy in belatacept rejection, and as a maintenance therapy in combination with belatecept.
mTOR Inhibitor Therapy Diminishes Circulating CD8+ CD28− Effector Memory T Cells and Improves Allograft Inflammation in Belatacept-Refractory Renal Allograft Rejection
Cyd M. Castro-Rojas, Ph.D.1, Alzbeta Godarova, Ph.D.1, Tiffany Shi, B.S.1, Sarah A. Hummel, M.A.1, Adele Shields, PharmD2, Simon Tremblay, PharmD, Ph.D.2, Rita R. Alloway, PharmD3, Michael B. Jordan, M.D.1,4,5, E. Steve Woodle, M.D.2,*, David A. Hildeman, Ph.D.1,5,*
Transplantation. 2020 May ; 104(5): 1058–1069.
A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation
Gretchen de Graav, MD1, Carla C. Baan, PhD1, Marian C. Clahsen-van Groningen, MD, PhD2,..
Transplantation, 2017
Its about memory cells, NOT about costimulation blockade
Memory T cells may mediate transplant rejection in addition to generating protective immunity. Donor-specific memory T cells are widely known to cause “second-set” rejection, which is exceedingly difficult to prevent, and all precautions are taken currently to avoid this situation in clinical transplantation.
Memory T cells alone are enough to cause rejection in animal models; they are among the first cell types to infiltrate the grafts, and memory T cells do not need secondary lymphoid tissues to acquire effector activities.
Furthermore, Tcm and Tem cells seem to mediate the rejection response in a similar way.
Current immunosuppressive medicines that are successful at suppressing naive T cells have a modest impact on memory T cell-mediated rejection, demonstrating that memory T cell activation differs significantly from naive T cell activation in rejection.
In fact, there is a substantial link between the existence of alloreactive memory T cells before transplantation and acute rejection episodes that occur despite tacrolimus and sirolimus-based therapy. Furthermore, depletion therapy (e.g., anti-thymocyte globulin or ATG) are less successful in removing memory T cells that are already present.
Memory CD4+ T cells are a major cell type that remains after depletion therapy and are capable of starting rejection events. The capacity of memory T cells to react to alloantigens in vitro has been shown to be inhibited by routinely used immunosuppressive medications in several investigations.
However, poor transplant results in individuals with a high memory T cell frequency show that traditional immunosuppressive medicines have limited in vivo effectiveness in patients with memory T cells.
Lakkis FG, Sayegh MH. Memory T cells: a hurdle to immunologic tolerance. J Am Soc Nephrol. 2003;14:2402. [PubMed] [Google Scholar]
Page AJ, Ford ML, Kirk AD. Memory T-cell-specific therapeutics in organ transplantation. Curr Opin Organ Transplant. 2009;14:643.
Thank you for sharing this fact: ” Memory T cells alone are enough to cause rejection in animal models; they are among the first cell types to infiltrate the grafts, and memory T cells do not need secondary lymphoid tissues to acquire effector activities.”
Dear All
Let us challenge you with a timely topic.
What are your thoughts about the memory cell functions in renal transplant recipients receiving the COVID-19 vaccine? Respond with references
Kidney transplant recipients demonstrate an impaired humoral and cellular immunity, which correlated with the type and number of immunosuppressive agents
Julian STS, Tom L, Claudia K, et al. Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: a prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine. Lancet Reg Health Eur 2021. doi: 10.1016/j.lanepe.2021.100178.
How the impaired memory cell function affects the response to the vaccine? Which type of IS would mainly affect this response to the vaccine?
Covid vaccine in kidney transplantation patients
Corticosteroid
Evidences from other vaccines, prolonged exposure to prednisolone might not influence the efficacy.
Lode et al. demonstrated that the efficacy of the pneumococcal vaccine was not influenced by the chronic use of prednisolone.
The efficacy of the vaccine might be better during the maintenance stage after transplantation. A booster injection with more than the regular dose might be considered
Calcineurin inhibitors
Ilies et al. showed that patients with maintenance use of CNIs had a less seropositive response after the 1st dose of an mRNA vaccine.The second dose should not be delayed in KT patients.
Observational study by Rahamimov et al. found that the use of CNIs might influence the seroresponsiveness to an mRNA vaccine. Patients with higher serum concentrations of >7 ng/mL for tacrolimus and >150 ng/mL for cyclosporine were more common among those without a serologic response.
CNI users should receive vaccination, and a higher dosage of immunosuppressive agents and a lower GFR might predict a poor response to the vaccine.
Mycophenolic acid (MPA)
MPA directly decrease the proliferation and maturation of T cell. The maturation and differentiation of B cells are also disturbed by MPA.
Haneda et al. showed that MPA could influence early B cell proliferation, so production antibodies would be decreased in MPA patients . The effect of MPA on the neutralizing antibody titer induced by the covid vaccine .
Rahamimov et al. showed that a lower mycophenolic acid dose was associated with higher responsiveness to the Covid -19 vaccine..
mTORI
Garcia Jr. et al. stated that the cytokine storm mediated by Covid is highly dependent on the mTOR-phosphatidylinositol 3-kinase (PIK)- protein kinase B (Akt) pathway.
mTORis might play role in COVID infection by reducing the cytokine storm.
Rahamimov et al. did not demonstrate the nonresponsiveness of antibodies in mTORi patients
Hou, Y., Lu, K. and Kuo, K., 2021. The Efficacy of COVID-19 Vaccines in Chronic Kidney Disease and Kidney Transplantation Patients: A Narrative Review. Vaccines, 9(8), p.885.
Humoral response to the 2 doses of COVID 19 vaccine among solid organ transplant recipients, the majority had detectable antibody responses after the second dose, although participants without a response after dose 1 had generally low antibody levels. Poor humoral response was persistently associated with use of antimetabolite immunosuppression.
To date, only one study has directly compared humoral immune responses to COVID19 between transplant and non-transplant recipients with and without COVID-19. Using banked samples from uninfected kidney transplant recipients as negative controls, this study of 18 kidney transplant recipients with symptomatic COVID-19 found that most patients exhibited broad activation of B cell subsets (switched, activated, and memory) but not T follicular helper (TFH) cells.
Furthermore, assessing the humoral response does not tell the whole story; both memory B cell and T cell responses play a role in protective immunity. Assessing the humoral response alone may underestimate the vaccine efficacy, particularly in transplant recipients.
References:
JAMA. 2021;325(21):2204-2206. doi:10.1001/jama.2021.7489
JAMA. 2021;325(17):1784-1786. doi:10.1001/jama.2021.4385
Am J Transplant. 2020 Aug 12 : 10.1111/ajt.16261.doi: 10.1111/ajt.16261
Kidney360 September 2021, 2 (9) 1402-1404; DOI: https://doi.org/10.34067/KID.0005352021
The question was about the memory cells’ function!! In COVID-19, we have both cellular and humoral responses. Which comes early, which will wane, and which will sustain?
The memory cells activity after COVID 19 vaccination based on results appeared in Science on September 14, 2021.-The Moderna and Pfizer mRNA vaccines against COVID-19 have shown greater than 90% effectiveness soon after the second dose . Research team at the La Jolla Institute for Immunology looked at immune memory six months after vaccination.-Levels of antibodies, CD4+ T cells, and CD8+ T cells remained strong six months after receiving the vaccine. This was found even among participants over 70 years of age, who are particularly vulnerable to severe COVID-19. Memory CD4+ T cells were still present in nearly everyone six months after full vaccination. Memory CD8+ T cells were detected in 67% of participants six months after full vaccination.
In patients with kidney transplantation on imunosuppression:
At base line, B cell lymphopenia has been described for DP and KTR and might affect proper humoral immune responses.
Kidney transplant recipients and dialysis patients show a markedly diminished humoral response and impaired molecular B cell memory Formation upon vaccination with data have described a lower serological response to an mRNA vaccine in dialysis patients and kidney transplant recipients.
REFERENCES:
Excellent, Thank you
I) Memory cells exhibit the following criteria :
⦁ Memory cells are either B or T cells
⦁ In appearance they are identical to mature resting cells
⦁ Memory cells are formed after exposure to foreign antigen, and can persists for decades after primary exposure , for example memory T cells can persist for 25 years or more.
⦁ They are very sensitive and react rapidly to previously encountered antigen than naive cells.
⦁ They are responsible for secondary immune Reponses with production of powerful high affinity antibodies
⦁ Alloreactive T cells constitute 60 % of T cells, Moreover, population of memory T cells expand with aging on the expense of naïve T cells (1)
⦁ Play very important rule in protection against invading pathogens especially if patient is under immunosuppression
II) In renal transplantation generation of alloreactive memory T cells occur through 3 mechanisms :
1- After primary immune response to the graft, constitute the main mechanism (2)
2- In response to lymphopenia (especially after T cell depleting therapy) (3)
3- Cross reaction due to similarity in donor MHC molecules and infectious antigens (4)
Memory cells to HLA antigens may be preformed due to pregnancy, previous blood transfusions or previous transplantations, or may arise after transplantation.
III) Why memory cells are important in renal transplantation?
1. Memory cells has lower activation threshold and persist for long time when compared to naive cells (5)
2. Memory cells are resistant to co-stimulation signals that mean they require lower costimulatory signals for being recalled
3. Memory cells are resistant to regulatory T cells (6)
4. They are not suppressed by conventional immunosuppressive drugs
5. Highly resistance to induction of tolerance
Thus alloreactive memory cells constitute a significant challenge when transplanting a foreign graft. Currently transplantation is depending on negative cross match between donor and recipient and HLA matching , but this may be misleading as it ignores the rule of memory cells in future graft rejection. thus traditional immunosuppression may has good effect on short term graft survival, but long term graft survival may be lower due to memory cells
IV) Mechanism of rejection by memory cells
Rejection occurs either due to Alloantigen-dependent or alloantigen-independent factors (tissue injury such as ischemic injury leading to upregulation of expression of adhesion molecules, or shedding of intact HLA )
Either Allo-antigen independent or dependent factors activate the immune response in the following way:
1- Donor-reactive memory CD4+ T cells are 2 types T helper 1 that activate macrophage leading to delayed type hypersensitivity and T helper 2 that provide CD-40 independent help to B cells mediated by B cell activating factor (BAFF) and CD-4 T cell IFN-γ leading to transformation of B cells to plasma cells that produce DSA.(7)
2- Alloreactive CD8-positive T cells that produce cell-mediated cytotoxicity (kill the cell or induced apoptosis)
3- Alloreactive B cells promote T cell proliferation, activation and differentiation
Two-signal are required for T cell activation
⦁ Signal 1 occur when antigen peptide- MHC complex located on APC is attached to TCR
⦁ Signal 2 occur when one or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called co-stimulation, CD28 stimulate, while CTLA-4 suppress T cells
V) Interventions that target memory cells
Currently the only available therapy is depleting T cells using ATG, ATG cause depletion of T cells, although ATG induced lymphopenia Triger generation of alloreactive memory T cells, but it was found that ATG significantly increase T regulatory cells which suppress memory T cells, So better survival of graft was obtained by ATG induction (8)
Potential memory T cell directed therapy based on animal studies
1- Targeting blocking of infiltration of alloreactive T cells into the graft by sequestering T cells in lymph nodes using 2 drugs :
⦁ FTY720 although it decrease infiltration of alloreactive T cells into the graft but could not blocks activation of B cells by CD4- T helper cells, leading to formation of DSA and graft loss (37)
⦁ anti-LFA-1 agent (Efalizumab) also it decrease infiltration of alloreactive Tcells into the graft , but increase risk of EBV-associated malignancy (9)
2- Targeting suppression of proliferation of alloreactive T cell :
⦁ Tofacitinib (CP-690550), a JAK-3 inhibitor which is responsible for cytokine release that aid in T cell proliferation, was found to prevent graft rejection (10).
3- Targeting inhibition of activity of alloreactive T cells :
⦁ Memory cells are resistant to co-stimulation signals, but it was suggested that there are other costimulatory pathways for memory T cells.
⦁ Blockade of the 4-1BB and OX40/OX40L costimulatory pathway was found to increase survival of skin, heart grafts (11,12)
4- Targeting memory B/T cell interaction :
⦁ Neutralization of BAFF with anti-CD154 monoclonal antibody and IFN-γ with anti-IFN-γ antibody was found to improve graft survival (13, 14). this may be particularly importent in renal transplant recipients at risk of generation of denovo DSA
REFERANCES
1- Emerson RO, Mathew JM, Konieczna IM, Robins HS, Leventhal JR. Defining the alloreactive T cell repertoire using high-throughput sequencing of mixed lymphocyte reaction culture. PLoS ONE. (2014)
2- Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol (2012) 12:749–61.
3- Sprent J, Tough DF. Lymphocyte life-span and memory. Science (1994) 265:1395–400.
4- Tchao NK, Turka LA. Lymphodepletion and homeostatic proliferation: implications for transplantation. Am J Transplant (2012) 12:1079–90. doi:10.1111/j.1600-6143.2012.04008.x
5- Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but conditional, role of OX40 in memory T cell-mediated rejection. J Immunol (2006) 176:1394–401. doi:10.4049/jimmunol.176.3.1394
6-Yang J, Brook MO, Carvalho-Gaspar M, Zhang J, Ramon HE, Sayegh MH, et al. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci U S A (2007) 104:19954–9.
7- Rabant M, Gorbacheva V, Fan R, YU H, Valujskikh A. CD40-independent help by memory CD4 T cells induces pathogenic alloantibody but does not lead to long-lasting humoral immunity. Am J Transplant (2013) 13:2831–41.
8- Ayasoufi K, YU H, Fan R, Wang X, Williams J, Valujskikh A. Pretransplant antithymocyte globulin has increased efficacy in controlling donor-reactive memory T cells in mice. Am J Transplant (2013) 13:589–99.
9- Kwun J, Farris AB, Song H, Mahle WT, Burlingham WJ, Knechtle SJ. Impact of leukocyte function-associated antigen-1 blockade on endogenous allospecific T cells to multiple minor histocompatibility antigen mismatched cardiac allograft. Transplantation (2015).
10- Paniagua R, SI MS, Flores MG, Rousvoal G, Zhang S, Aalami O, et al. Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation (2005) 80:1283–92.
11- Cho HR, Kwon B, Yagita H, LA S, Lee EA, Kim JE, et al. Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival. Transpl Int (2004) 17:351–61.
12- Wang GM, Yang Y, Jin YZ, LI AL, Hao J, Gao X, et al. Blockade of both CD28/B7 and OX40/OX40L co-stimulatory signal pathways prolongs the survival of islet xenografts. Transplant Proc (2005) 37:4449–51.
13-Gorbacheva V, Ayasoufi K, Fan R, Baldwin WM III, Valujskikh A. B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. Am J Transplant (2015) 15:346–57.
14- Gorbacheva V, Fan R, Wang X, Baldwin WM III, Fairchild RL, Valujskikh A. IFN-gamma production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol (2015) 194:1347–56.
Thank you,
Please recheck references.
Why do you think all these medications failed to demonstrate benefits in the clinical transplantation arena?
Because memory cells are different from native cells. It is more sensitive to antigens stimulation, Have more powerfull immune response, resistant to T regulatory cells, resistant to costimulation signals and so resistant to drugs acting on this mechanism, Moreover immunospression induced lymphopenia increase its production.
Presence of pseudomemory T cells which are antigen independent and not
need costimulation in process of homeostatic reconstitution these functionallly activated t cell reduce depletion effect of drugs.
Immunological memory is able to make a rapid and robust immune reaction against a reinvaded antigen, so it protects the body from huge number of pathogens after infections or vaccinations. This long-lasting protection is caused by both cellular and humoral adaptive immune responses, therefore the long-lived memory T and B cells have pivot role in immunological memory.
These cells come from clonal expansion of naïve cells during primary immune responses, and can last for many years after eradication of the pathogen.
Memory B and T cell can destroy the transplantation by enhancing vigorous immune reaction against the donor Kidneys. They result from exposure to allogeneic HLA to blood transfusions, pregnancies or previous transplantations.
☆Alloreactive T cells
Alloreactive T cells have a major role in induction of graft rejection as they contribute to both acute and chronic rejection depending on the pathway utilized to recognize donor antigens (both major and minor histocompatibility antigens).
☆ Alloreactive B Cells
Antibody mediated rejection (ABMR) is caused by humoral alloimmunity and considered as a principal cause of graft failure in kidney transplantation. Interaction between alloreactive T and B cells plays a key role in the generation of full-blown humoral alloimmune responses
☆ Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response. The costimulatory pathway is not targeted with the conventional immunosuppressive therapy. Biologicals that intervene with the costimulatory pathway may allow more precise targeting of the immune response without causing non-immune adverse events.
Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success.
Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients.
In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection.
☆ Alternative Approaches of Costimulation Blockade
CD28 Antibodies: FR104 and lulizumab-pegol
CD2/SLAM Family Antibodies: Alefacept
CD40/CD154 (CD40 Ligand) Antibodies: Iscalimab and Bleselumab
☆ Reference
• Van der Zwan, M., Hesselink, D.A., van den Hoogen, M.W.F. et al. Costimulation Blockade in Kidney Transplant Recipients. Drugs 80, 33–46 (2020). https://doi.org/10.1007/s40265-019-01226-6
• Karahan GE, Claas FHJ and Heidt S (2020) Pre-existing Alloreactive T and B Cells and Their Possible Relevance for Pre-transplant Risk Estimation in Kidney Transplant Recipients. Front. Med. 7:340. doi: 10.3389/fmed.2020.00340
Timeline of the development of costimulation blockade
The question here is about Memory Cells and not on Costimulation Blockade!
Memory T-cell (TM) have been divided into central memory T cell (Tcm) expressed lymphoid markers CCR7and CD62L and effector memory T cell (Tem)which expressed molecules that promote migration in peripheral tissue 1,2.
Some studies showed that some T cells in peripheral tissues don’t circulate and represent a distinct subset of tissue-resident memory T cells (Trm) 3,4.Trm play an important role in host protection against infection.Trm of both donor and recipient origin may influence transplant outcome by facilitating GVHD and allograft rejection.
Another type of memory T cell is CD+4CXCR5hi follicular helper cell (Tfh)which resides in B cell follicles within secondary organs and is essential for optimal B cell response and antibodies generation 5.
TM has several advantages over naïve T lymphocytes. They are present at a much higher frequance and have alonger lifespan, wider migration pattern ( they migrate to and reside in either lymphoid or nonlymphoid organs) and lower threshold for activation than naïve T lymphocyte. TM generate a much stronger immune response(recall response )than that of naïve T lymphocyte (primary response).
Humans acquired TM for 3 reasons:
-First, it is generated in response to vaccination or infection is frequently cross-reactive with alloantigens.
-Second, it arises after exposure to alloantigen in blood transfusion, prior organ transplant, or pregnancy.
-Third, it emerges during recovery from lymphopenia.
The strategies attempted to suppress TM :
-Lymphoablation
Induction therapy is widely used in clinical transplantation, antibody –mediated lymphocyte depletion is the most commonly used induction strategy, particularly in highly sensitized patients and the patient who received marginal grafts 6-7. Although TM is the primary target for induction therapies they are less susceptible to depletion than naïve T cell 8-9, anti CD52 Campath or ATG are associated with acute rejection episodes.
–Metabolic pathway
Manipulating T cell survival and homeostasis by regulating cell metabolic pathways may be a promising therapeutic strategy in transplantation. Some studies showed that immune cell subsets use different mechanisms of energy generation and this to selectively target undesirable memory T cells.
–Costimulatory Blockade
Belatacept, CTLA4-Ig, is used to prevent allograft rejection and minimize toxic side effects of calcineurin inhibitor but it has a higher rate of acute cellular rejection compared to CNI treatment.T M is more resistant to belatacept.
–Limiting Trafficking of alloreactive T M.
References
1.Farber DL. Heterogeneity of the memory CD4 T cell response: persisting effectors and resting memory T cells. J Immunol (2001) 166(2):926–35.10.4049/jimmunol.166.2.926 [PubMed] [CrossRef] [Google Scholar]
2. Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol (2003) 4(3):225–34.10.1038/ni889 [PubMed] [CrossRef] [Google Scholar]
3. Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity (2013) 38(1):187–97.10.1016/j.immuni.2012.09.020 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
4 .Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, Beura LK, et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol (2012) 188(10):4866–75.10.4049/jimmunol.1200402 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5.Hale JS, Ahmed R. Memory T follicular helper CD4 T cells. Front Immunol (2015) 6:16.10.3389/fimmu.2015.00016 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
6.Fehr T, Sykes M. Tolerance induction in clinical transplantation. Transpl Immunol (2004) 13(2):117–30.10.1016/j.trim.2004.05.009 [PubMed] [CrossRef] [Google Scholar
7. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia (2007) 21(7):1387–94.10.1038/sj.leu.2404683 [PubMed] [CrossRef] [Google Scholar]
8.Koyama I, Nadazdin O, Boskovic S, Ochiai T, Smith RN, Sykes M, et al. Depletion of CD8 memory T cells for induction of tolerance of a previously transplanted kidney allograft. Am J Transplant (2007) 7(5):1055–61.10.1111/j.1600-6143.2006.01703.x [PMC free article] [PubMed] [CrossRef] [Google Scholar]
9.Zeevi A, Husain S, Spichty KJ, Raza K, Woodcock JB, Zaldonis D, et al. Recovery of functional memory T cells in lung transplant recipients following induction therapy with alemtuzumab. Am J Transplant (2007) 7(2):471–5.10.1111/j.1600-6143.2006.01641.x [PubMed] [CrossRef] [Google Scholar
10. Danovitch G.M handbook of kidney transplantation sixth edition
A large number of effector lymphocytes are generated during an immune response, but most undergo activation-induced cell death (AICD) by apoptosis as the response progresses. The few effector lymphocytes that survive give rise to memory T lymphocytes (TM)
In humans, they consist of two major subsets: central memory (TCM) and effector memory (TEM).
TM constitute approximately half of the alloreactive T-lymphocyte repertoire in human
TM lymphocytes generate a much stronger immune response (recall response) than that of naïve T lymphocytes (primary response).
B lymphocytes and their progeny, the plasma cells, are the immune cells responsible for antibody production
Naïve B-lymphocyte activation is dependent on antigen recognition by the B-cell receptor (BCR) and on critical help from the TFH subset of CD4+ T lymphocytes inside secondary lymphoid organs
B lymphocytes that receive all the necessary stimulatory signals coalesce in the follicles to form germinal centers. There, they proliferate extensively, undergo affinity maturation, and differentiate into plasma cells and memory B lymphocytes
Plasma cells are antibody factories and, along with memory B lymphocytes, maintain long-term humoral immunity
Strategy
1-Total lymphoid elimination protocols: Tolerance is achieved by irradiating the lymph nodes, spleen and thymus. Clinical application therefore is limited due to the high toxicity of this kind of treatment. At present, it is limited to use in patients with multiple myeloma and co-existing end stage renal failure to induce a state of lympho-haematopoietic chimerism.
2-Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance. This strategy was commonly used in Japan for ABO incompatible transplant.
AND THESE ARE SOME PROTOCOLS FOR CELUUAR
1- T cell depletion like
a-ATG: T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis, modulation of key cell surface molecules, induction of apoptosis in B-cell lineages, interference with dendritic cell functional properties, induction of regulatory T and natural killer T cells
b- Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
2-Other T cell therapies
Basiliximab: Blockade of CD25 Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and stabilise the expression of FoxP3
3-B cell therapies
a-Rituximab: Depleting monoclonal antibody to CD20 Belimumab: Blockade of BAFF B cell activating factor causing depletion of follicular and alloreactive B cells, decrease in alloantibody response and promotion of immature/transitional B cell phenotype
b-Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand)
c- Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
d-Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
4-Costimulation blockad
a-Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
b-Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
memory B cells represent the ultimate outcome of humoral immunity. Many of these cells express exceptionally high affinity antigen-specific B cell receptors for antigen, and these cells are a critical source of the long-lived plasma cells that secrete protective serum antibodies to protect against secondary exposure to pathogens and other life-threatening antigens. Evidence is now emerging that not all memory B cells are created via the same cellular pathways and molecular events. Similarly, it is becoming clear that different memory B cells can take on different functions, with some producing IgM rather than IgG antibodies upon reactivation, and others preferentially producing plasma cells rather than additional waves of memory B cells.[1]
In humans, the presence of memory T cells pretransplantation has been associated with an increased risk for acute rejection of kidney transplants . However, while EBV- and CMV-specific memory T cells displaying alloreactivity have been detected in human transplant recipients, so far there is no indication that the presence of “heterologous immunity” in transplant recipients correlates with worse graft outcomes
– Induction therapy is widely used in clinical transplantation to overcome the deleterious effects of preexisting donor-reactive immunity. Antibody-mediated lymphocyte depletion is most commonly used induction strategy, particularly in highly sensitized patients and in patients receiving marginal grafts. Although memory T cells are the primary targets of induction therapies, they are less susceptible to depletion than naïve T cells. T cells with an effector/memory phenotype are detectable after anti-CD52 mAb or ATG induction and are associated with acute rejection episodes in non-human primates and human transplant recipients
– Belatacept, a second generation of CTLA4-Ig, is currently used in clinical transplantation to prevent allograft rejection and minimize the toxic side effects of calcineurin inhibitors. Despite reduced side effects and improved graft survival, belatacept-treated patients have higher rates of acute cellular rejection compared to CNI treatment
– a short course of integrin blockade may be instrumental in controlling T cell memory while avoiding side effects of long-term treatments. [2]
[1] Mary M Tomayko and David Allman
Current Opinion in Immunology, 2019-04-01, Volume 57, Pages 58-64, Copyright © 2019
[2] Role of Memory T Cells in Allograft Rejection and Tolerance Front Immunol. 2017; 8: 170.
Published online 2017 Feb 28. doi: 10.3389/fimmu.2017.00170