What is meant by tolerance in your own words? Have we managed to achieve tolerance?
Alyaa Ali
3 years ago
Tolerance ; is a state of permanent immunological acceptance of allograft by the host immune system in the absence of immunosuppression. Self tolerance : as T cells and B cells undergo education and maturation in the central lymphoid tissues ,during this process T and B cells learn to differentiate between self and non self antigen .it is a kind of surveillance mechanism to prevent expansion of potentially harmful auto reactive T and B cells .
1.central tolerance in which potentially auto reactive T and B cells are removed by anergy , deletion and receptor editing
2.peripheral tolerance : sweeper mechanism of destroying these self reactive T and B cells that escaped central tolerance through deletion ,apoptosis , energy and regulation or suppression
the main mediators for tolerance are
a.thymus derived regulatory T cells responsible for central tolerance
b. peripherally derived regulatory T cells responsible for peripheral tolerance
c.induced regulatory T cells in vitro Tolerance signatures or biomarkers
tolerant patients showed the following criteria :
1.expansion of peripheral blood B and NK cells
2.fewer activated CD4+ T cells
3.lack of DSAs
4.donor specifc responsiveness of CD4+ T cells
5.higher rate of FoxP3 to alpha 1 and 2 mannosidase gene expression Chimerism is co-existence of donor and host haematopiotic stem cells inside the host without inducing an immunological reaction against donor cells. as occur in transplantation between genetically identical monozygotic twins
Micro chimerism : is persistence of a small number of donor cells less than 1% of all circulatory cells within recipient body leading to spontaneous operational tolerance.
this may occur in liver transplant due to leukocytes coming within the transplanted organ Tolerogenic strategies
cell therapies
T cell depletion , co stimulation blockade
or current cellular therapy in development as mixed chimerism , regulatory T cells or B cells
2.total lymphoid tissue elimination protocols by irradiation of lymph nodes , spleen and thymus ,but clinical application is limited due to toxicity
3.splenectomy especially in ABO incompatible patients Successful protocols to achieve tolerance
achieving full donor chimerism
achieving transient mixed chimerism
achieving sustained mixed chimerism
saja Mohammed
3 years ago
Summary:
—————-
The word tolerance come from the original latin term tolera its indicate the condition when a-forieng tissue or organ engrafted in a-host with clinical and immunological accepatncein the abscence of immunsuppressions.
still alot of researches are ongoing in this field of transplant immunology and its the dream and hope to most of us to reach the state oragn tolerance with out the side effect and cost of the currnet immunsuppressions
Self tolerance :
both T and B cells controls the immune system protecting the host from foreign pathogens which have important role in self-tolerance and non -self( foreign ) tolerance
induction of tolerance involve many mechanisims at the cellular levels both T and B Cells after migartion to the peripheral lymphiod tissues in the precence of TCR and antigenic activation to CD4-CD8 T-cells, which called double postive thymocytes and according to the avidity ofself response will undergo either negative clonal depletion by apoptosis or postivesingle clonal selction .
Central tolerance:
is the most important process by which
the potentially auto-reactive T and B cells are eliminated by a
process called clonal deletion .
Thymus-derived regulatory T (tTreg) cells are considered main mediators of central immune tolerance, whereas peripherally derived regulatory T (pTreg) cells function to regulate peripheral immune tolerance. A third type of Treg cells, termed iTreg, represents only the in vitro-induced Treg cells. peripheral tolerance:
Peripheral tolerance is the sweeper mechanism of destroying those self-reactive T and
B cells that somehow escaped central tolerance mechanism and end up in the peripheral
circulation. Tolerance signature:
pontaneous operational tolerance has been achieved in non-adherent transplant patient, buarad etal reported 27 cases of traplsnat tolerance
Immunosuppression may affect ‘Tolerance signatures’ and biomarkersof tolerance includes the following -Differential expression of B-cell related genes. – Expansion of peripheral B-cells and NK cells. – Few activated CD4+ve cells. – Lack of DSA. – High ratio of Foxp3 / alpha1,2 mannosidase gene expression.
– Chimirsim
means an acquired Tolerance. co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerance startagies :
-Trials of Cellular therapies in development
–Tolerance is achieved by irradiating the lymph nodes, spleen and thymus.
-Splenectomy
Ahmed Omran
3 years ago
Immune tolerance is the survival of non-self tissue or organ without immunosuppression. It includes complex and poorly understood mechanisms. One major agent in mediating tolerance is Tregs, of which 2 types are known;t Tregs & p Treg). If immune-tolerance is achieved without serious hazards, it will lead to revolution in transplantation , because of prolonged graft survival without serious morbidity and mortality due to IS.
Self-tolerance occurs during early fetal life with lymphocyte maturation in central lymphoid organs .Immature T-cells will acquire TCR and CD4 or CD8 antigens in the thymus to mature and reactive T-cells, called double +ve thymocytes. The later will react with peptides in the thymic stroma with different degrees. The strong reactive T-cells will undergo apoptosis, called -ve selection .Very low reactive cells will die in the thymus. Remaining cells with favorable reactivity will undergo +ve selection and this proportion represents 3-5 % of total lymphocytes.
Biomarkers of tolerance have been described and include the following :
– Differential expression of B-cell related genes.
– Expansion of peripheral B-cells and NK cells.
– Few activated CD4+ve cells.
– Lack of DSA.
– High ratio of Foxp3 / alpha1,2 mannosidase gene expression.
Chimerism has been described as co-existence of donor and host stem cells inside the host without induction of immune response. Different protocols have been tried for induction of chimerism like :
– Full donor chimerism.
– Transient mixed chimerism.
– Sustained mixed chimerism.
Tolerogenic strategies have been developed to induce tolerance and include the following :
– Cellular therapies as total lymphoid elimination by irradiation of the thymus,
spleen and lymph nodes. however, this therapy is highly toxic.
– Splenectomy as spleen is important in B-cell maturation and IgM production.
Ibrahim Omar
3 years ago
Immune tolerance is the ability of non-self tissue or organ to survive without immnuosuppression. it involves a complex and poorly understood mechanisms for its achievement. one major culprit in mediating tolerance is Tregs, of which 2 types are known (t Tregs and p Tregs). if immune tolerance is adequately achieved without serious hazards, a revolution in transplantation will occur, because of prolonged graft survival without serious morbidity and mortality of immunosuppression.
Self-tolerance already occurs during early fetal life with lymphocyte maturation in central lymphoid organs (thymus & lymph nodes). immature T-cells will acquire TCR and CD4 or CD8 antigens in the thymus to become mature and reactive T-cells, called double +ve thymocytes. the later will react with peptides in the thymic stroma with variable degrees. the too strong reactive T-cells will undergo apoptosis, called -ve selection. also, the very low reactive cells will die in the thymus. the remaining cells with favorable reactivity will undergo +ve selection and this proportion represents 3-5 % of the total lymphocytes.
A number of biomarkers of tolerance have been described and include the following :
1- differential expression of B-cell related genes.
2- expansion of peripheral B-cells and NK cells.
3- few activated CD4+ve cells.
4- lack of DSA.
5- high ratio of Foxp3 / alpha1,2 mannosidase gene expression.
Chimerism has been described as co-existance of donor and host stem cells inside the host without induction of immune responce. variable protocols have been tried for induction of chimerism and include :
Some tolerogenic strategies have been developed to induce tolerance and include the following :
1- cellular therapies as total lymphoid elimination by irradiation of the thymus,
spleen and lymph nodes. however, this therapy is highly toxic.
2- splenectomy as the spleen is critical in B-cell maturation and production of
IgM. it was used in Japan for ABO incompatible grafts. however, the spleen
is also important for development of Tregs.
Wael Hassan
3 years ago
First of all tolreance is our dream in kidney tansplantation
Tolerance means that the ability of foreign tissue or organ to survive in host without immunosuppressant
Means permanent acceptance of allograft by host immune system in the absence of immunosuppressant
-self tolerance
T&B cells learn to differentiate between self and foreign AG
-central tolerance
T&B lymphocytes mature in thymus &bonemarrow When it reach thymus immature cell undergo rearrangement process to become double positive thymocyte that react with self peripheral protein to eliminate cells with strong reaction to elicit benine Cells for maturation to become single positive Tcell
-peripheral tolerance
Sweeper of T&B cells that escape central tolerance
-tolerance signature
Patient on immunosuppressant have different signature ( biomarker)from patient not recieved
-chimerism
Co existence of donor &recipient heamtopoitic stem cell inside recipient without immunological response.
Noted in cattle twins shared common placenta red cell chimerism extended to adulthood , indicate that exposure to non self AG in utero on neonatal can led to micro chimerism.
Tolerance strategies:
– total lymphoid elimination (limited use in M.M
-spleenectomy;done in japan in ABO incompatibility
-T-cell depletion by ATC or alemtozumab
-costimulation blockade by belatacept or efalizumab
-other T-cell therapies as basileximab ( interlukin 2 antagonist)
-Rituximab ,belimumab,atacicept ( B-cells)
-bortizomab apoptosis of plasma cells
-Eculizumab anti interlukin 6
Mixed chimerism
-infusion of donor bone marrow into recipient for producing co-exsitance of donor and recipient cells.
-regulatory T-cell,dendritic cells,regulatory B-cell,macrophages,myloid derived suppresor cell
Full chimerism:
-MGH protocol: HLA matched related donor kidney &bone marrow transplant for heamatogic malignancy .
-MGH protocol: haploidentical donor kidney &bone marrow transplant in heamatogic malignancy .
-North western protocol:haploidentical /mismatch related& unrelated kidney & bone marrow transplant for ESRD without malignancy.
Balaji Kirushnan
3 years ago
Tolerance is the ability of an organ to survive in a foreign individual without any immunosuppression. It is basically a donor specific non reactivity by the recipient. Clinical tolerance is defined as a well accepted graft lacking signs of histological rejection for atleast 1 year after transplant. The concept of tolerance is best understood through learning about self tolerance. In the developmental process of the lymphoid tissue both T cells and B cells undergo education and maturation in the central lymphoid organs (bone marrow and thymus). During this process T and B cells learn to differentiate between self and non self.
Central tolerance is a process by which potential autoreactive T cells and B cells are eliminated by clonal deletion. Anergy – if signalling through the BCR is sufficiently weak, immature B cells can be rendered permanently unresponsive. If the B cells or T cells are strongly self reactive, they are deleted. Rarely BCR can undergo editing and altered specificity is generated
peripheral tolerance: Those T cells and B cells which escape the clonal deletion process in the central lymphoid tolerance are captured by the mechanism of peripheral tolerance.
Deletion and apoptosis – Apoptosis induced cell death is mediated by binding of
Fas (CD95) with its ligand FasL (CD 95L) on T Cells Anergy – Hyporesponsiveness of T or B cells to further antigenic stimulation in the
absence of costimualtion
Regulation and Suppression – it is done by T regulatory cells’ also called Treg
cells. which are either thymus derived or in the periphery
Tolerance is the holy grail in renal transplantation. Tolerant patients usually show expansion of peripheral blood B and NK lymphocytes, fewer activated CD 4 T cells, lack of DSA, donor specific hyporesponsiveness of CD 4 Tcells, high ratio of FOXP 3 gene expression. This study was published in 2010 and it showed the above as a measure of operational tolerance
The current strategies used for tolerance are
T cell depletion: using Antithymocyte Globulin and Alemtuzumab (anti CD 52)
Costimulation Blockade: Abatacept, Belatacept – blockade of CD 28:CD 80/86 pathway; Efalizumab – blockade of LFA1:ICAM1 co stimulatory pathway
Basiliximab – Blockade of CD 25
Rapamycin and aldesleukin – increase regulatory T cell proliferation and survival
B cell tolerogenic therapies : Rituximab – anti CD 20 monoclonal antibody ,Bortezomib – anti plasma cell inhibition, Belimumab – Blockade of BAFF Bcell activating factor, Atacicept: Blockade of BAFF and APRIL, Eculizumab – Blockade of complement protein C5
Chimerism: is state of coexistence of donor and host hematopoeitic stem cells inside the host without inducing an immunological reaction against donor cells. The phenomenon of microchimerism is when <1% of the donor cells are within the recipient body during blood transfusion, pregnancy and previous transplants. It is seen in 20% of liver transplants where a large number donor leucocytes come into the transplanted liver due to portal circulation
Chimerism can be full donor chimerism where 100% of bone marrow and blood cells are of donor origin. Mixed chimerism is when both donor and recipient hematopoeitic stem cells reside in the recipient without inducing an immunolgical reaction. Mixed chimerism can be sustained or transient. 3 universities namely MGH, Standford and North western University have published their vast experience in the field of chimerism and rena transplant to achieve tolerance. Total body lymphoid irradiation was used in MGH protocol in cases of multiple myeloma and coexisting ESRD. Many of these patients were off immunosuppressives after an average of 6 months after transplants. tolerance was achieved in a variable number from 40-60% across the 3 studies
Mohammed Sobair
3 years ago
Tolerance:
Inability of a foreign tissue or organ to survive in a host without immunosuppression. Clinical operational tolerance:
Is described as a well-functioning graft lacking histological signs of rejection in absence
of immunosuppression for at least 1 year in an immunocompetent.
Immunological tolerance:
No detectable immune reaction towards the allograft in absence of
immunosuppression. It is a state of permanent and specific c immunological acceptance
of the allograft.
Self-Tolerance:
T and B cells learn to differentiate between self-antigens and non-self (foreign antigen).
Central tolerance:
is the most important process by which the potentially auto-reactive T and B cells are
eliminated by a process called clonal deletion.
Peripheral tolerance:
Peripheral tolerance is the sweeper mechanism of destroying those self-reactive T and
B cells that somehow escaped central tolerance mechanism and end up in the
peripheral circulation.
Tolerance signatures:
Tolerant patients showed the following characteristics • expansion of peripheral blood B
and NK lymphocytes • fewer activated CD4+ T cells • lack of donor specific c antibodies,
Donor specific hypo responsiveness of CD4+ T cells • high ratio of FoxP3 to α-1, 2
mannosidase gene expression • differential expression of B cell related genes and
associated molecular pathways
Chimerism:
is co-existence of donor and host hematopoietic stem cells inside the host without
inducing an immunological reaction against donor cells.
Microchimeric:
Is persistence of a small number of donor cells (less than1% of circulating recipient cell)
in the recipient body.
Presence of such Microchimeric can occur from pregnancy, blood transfusion and
previous transplants
. Microchimeric leading to spontaneous operational tolerance has been seen in up to
20% of liver transplants.
Tolerance strategies:
Successful protocols with the aim of inducing tolerance in kidney transplant recipients
enabling immunosuppression to be discontinued.
Total lymphoid elimination protocols:
Tolerance is achieved by irradiating the lymph nodes, spleen and thymus.
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-hematopoietic chimerism.
Splenectomy:
Splenic irradiation or splenectomy resulting in a state of tolerance. This strategy was
commonly used in Japan for ABO incompatible transplants.
Cellular therapies:
T cell depletion
ATG: T-cell depletion in blood and peripheral lymphoid tissues through complement-
dependent.
Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
Costimulation blockade
Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
Other T cell therapies:
Basiliximab: Blockade of CD25.
Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and
stabilise the expression of FoxP3 B cell therapies
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
Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand).
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies in development.
Mixed chimerism:
Infusion of donor bone marrow into myoablated /immune-conditioned recipient for
producing co-existence of donor and recipient cells.
Regulatory T cells:
Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production,
down-regulate costimulatory and adhesion molecules, promote anergy and cell death,
convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL-
10,TGF-B and IL35.
Dendritic cells
Deletion of T cells, induction of Trigs and anergy T cells, expression of
immunomodulatory molecules and immunosuppressive factors.
Macrophages
Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and caspase dependent
depletion of activated T cells.
Myeloid derived suppressor cell
Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-
Y producing T cells
Mesenchymal stromal cells:
Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T
cells and downregulation of MHC Class II and co-stimulatory molecules
Regulatory B cells
Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM,
expression of Fas-L.
Successful protocols with the aim of inducing tolerance in kidney transplant
recipients enabling immunosuppression to be discontinued are :
Full donor chimerism protocol:
our main aim in kidney transplantation is to induce tolarance , wich means to make the host body to accept the graft as a self ( ORGAN ) antigen .
self tolerance : means that the lymphoid tissue ( T,B cells ) lern to recognize the patients antigens as aself one whithout inducing reaction against them .
central deletion : is the process of elimination of auto reactive B and T cells by clonal delletion .
CD4 foxp3 rg and CD4 foxp3 reg t1 ceel are important lines in the tolerance process .
chimersim : is the presence of both donor and host hematopoitic stem cells inside the host without induction any immunological reaction.
tolarogenic strateges :
Strategy
T cell depletion —
ATG AND ALEMTUZMAB
Costimulation blockade —- BELATOCEPT , ABATACEPT AND EFALIZUMAB
Other T cell —— Basiliximab , Aldesleukin + Rapamycin:
therapies
B cell therapies :
Rituximab , Belimumab , Atacicept , Bortezomib , Eculizumab .
CELLULAR THERAPY IN DEVELOPMMENT :
Mixed chimerism , Regulatory T cells , Dendritic cells , Macrophages , Myeloid derived suppressor cell , Mesenchymal stromal cells , Regulatory B
cells
THERE IS MANY DESIYNED PROTOCOLS AT DIFFRENT CENTERS WITH PROMISING RESULT .
Abdulrahman Ishag
3 years ago
Clinical operational tolerance, prescribed as well functioning graft with the following features;
1- no histological signs of rejection
2- off immunosuppressant for at least one year
3- host is immune competent
Immunological tolerance ; means no immune reaction towards the allograft in the absence of immunosuppressant.
Self tolerance; during early period of development T and B lymphocytes learn how to differentiate between self and none self antigens and it is classified into central and peripheral types.
Central tolerance; in which auto reactive T and B cells are eliminated by process called clonal deletion .
Clonal deletion of T cell; T cells mature in the thymus ,when they reach the thymus are lack (TCR ,CD4 and CD8)and are called double negative. In the thymus are incorporated with TCR and up regulated with CD4 or CD8 and are called double positive.
Double positive T cells start reacting with peptides in thymic stroma (self peripheral protein).
T cells that react too strongly with self peptide are eliminated by apoptosis (negative selection).
T cells that react favorably with self peptide are in turn positively selected and eventually become mature T cell that express either CD4 or CD8 receptor.
Cells with very low avidity interactions fail to induce survival signals and die within thymus.
3 – 5% of original T cells ,that enter the thymus are positively selected and end up as mature T cell.
Clonal deletion of B cell; the same like T cell.
Peripheral tolerance; is the mechanism of destruction of self reactive T and B cells ,that somehow escaped central tolerance mechanism, via one of the following mechanism; deletion ,apoptosis ,energy or (regulation or suppression )B cells .
Tolerance signature ;
Spontaneous tolerance has been achieved in none adherent patient.
Tolerant patients showed the following characteristics;
– Expansion of peripheral blood B and NK lymphocytes
– Fewer activated CD4+ T cells.
-Lack of donor specific antibodies. – Donor specific hyporesponsiveness of CD4+ T cells
– high ratio of FoxP3 to α-1,2 mannosidase gene expression.
– Differential expression of B cell related genes and associated molecular pathways Chimerism;
Co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells .
Microchimerism;
Persistence of a small number of donor cells within the recipient body ,which can occur from pregnancy ,blood transfusion and previous transplant .
It can lead to spontaneous operational tolerance.
●Tolerance is the ability of a foreign tissue or organ to survive
in a host without immunosuppression.
●“Immunological tolerance” is no detectable immune
reaction towards the allograft in absence of immunosuppression.
It is a state of permanent and specifi c immunological acceptance
of the allograft by the host immune system in the absence of
immunosuppression
●Self-tolerance: T and B-lymphocytes,
controls the immune system protecting the host from foreign
pathogens. In the developmental pathway of the lymphoid
system, T cells and B cells undergo education and maturation
in the central lymphoid organs; the thymus and bone
marrow. During this maturation process, T and B cells learn
to differentiate between self-antigens and non-self (foreign)
antigens
●Central tolerance
In the affinity-avidity model, self-tolerance comprises of
central and peripheral tolerance and can be described as a kind
of surveillance mechanism to prevent expansion of potentially
harmful auto-reactive T and B cell clones
●Peripheral tolerance
Peripheral tolerance is the mechanism of
Cleaning those self-reactive T and B cells that somehow
escaped central tolerance mechanism and end up in the
peripheral circulation. They are controlled in the periphery
by one of the following mechanisms: deletion and apoptosis,
energy, and regulation or suppression
●‘tolerance signatures’ ara biomarkers has been of
immense interest as validation of these biomarkers across
different set of populations will aid in formulating predictive
models for identifying those recipients that will achieve
tolerance with minimal or no immunosuppression long term.
●Chimerism
Chimerism is co-existence of donor and host haematopoietic
stem cells inside the host without inducing an immunological
reaction against donor cells.
●Tolerogenic Strategies :
1:Cellular therapies ; e.g. T cell depletion( ATG, Alemtuzumab, Basiliximab, Aldesleukin+ Rapamycin, Rituximab, Belimumab). Costimulation blockade( Abatacept, Belatacept, and Efalizumab). B cell therapy( Atacicept, Bortezomib)
2;Total lymphoid elimination protocols ; This protocol uses irradiation, and is more toxic therapy. The only indication is Multiple Myeloma+ ESRDSplenectomy; The idea is get rid of circulating antibodies. This technique is popular in Japan for ABO incompatible transplant. However current literature demonstrated the role of spleen in induction and maintenance of regulator CD4 T cell, and there fore induces self tolerance. Other therapies are in the stages of development.
●Successful Protocols with the aim of inducing tolerance in kidney transplant allowing immunosuppression to be withdrawn ;
Full donor chimerism ;
Transient mixed chimerism protocol ; Sustained mixed chimerism protocols ;
Jamila Elamouri
3 years ago
Tolerance:
Definition: tolerance is to have foreign organ survive in a host, without the use of immunosuppression.
Types: 1- Clinical operational tolerance
It is well functioning graft with no histological features of rejection without the use of immunosuppression drugs for at least one year in an immunocompetent host which is able to respond to infections or other triggers to the immune system. 2- Immunological tolerance
It is a state of complete immunological acceptance of the allograft by the host immune system without the use of immunosuppression.
Self-tolerance:
The lymphoid system, T-cells and B-cells during their maturation in the thymus and bone marrow learn to differentiate between self-antigen and non-self-antigens. It is oversight mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. It includes central and peripheral tolerance. Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
T-cell reach the thymus as immature cell which lack both the TCR and the antigen CD4 and CD8, this cell called double negative cell. In the thymus; incorporation of TCR with upregulation of the CD4 and CD8 to this cell occur, and this cell called double positive cell. Double positive T cells then react with the peptides in thymic stroma (self-peripheral proteins). T-cell than strongly react are eliminated by apoptosis (negative selection) while T-cells that interact positively to self-protein are selected positively and become mature T cells and express either CD4 or CD8 receptors, so become single positive T cells. this process is called clonal selection. T-cell with very low reaction fail to induce survival signals and die within the thymus. The mature T-cells leaving the thymus represent 3-5% of the original T cells. the B-cell as well undergo the test for reactivity to self-antigen before they are released to the periphery. The central immune tolerance is the function of thymus-derived regulatory T-cell (pTreg). Peripheral Tolerance is a mop mechanism of killing the self-reactive T and B cells that escape the central tolerance mechanism and enter the peripheral circulation. They are removed by either the deletion and apoptosis, energy, and regulation or suppression. The peripheral immune tolerance is done by the Peripheral regulatory T cells (pTreg).
Induced T regulatory cell (iT cell) induced in vitro, is a third type of Treg cells.
Another classification to Treg cell depend on what they express:
A- Classical CD4+ Foxp3+ Treg cells
B- CD4+Foxp3-type 1 regulatory t cell (Tr1)
These expressers become area of researches with promising hope to prevent transplant rejection. Tolerance signatures: (biomarkers)
Researchers show more interest in identification of the biomarkers of tolerance, as by validation of these biomarkers, there will chance to predict those recipients that will get tolerance with no immunosuppression or minimal dose.
tolerance signatures in kidney transplants include immunosuppression effect and differential expression of B-cell-related genes and relative expressions of B-cell subsets. Gene expression signature reliably identify patients suitable for immunosuppression drug reduction.
Brouard et al, have identified a composite score which discriminates operationally tolerant patients, the score is associated with both de novo anti-HLA antibodies and tolerance loss. Chimerism
It is living of the donor and host haematopoietic stem cells inside the host without causing an immunological reaction against donor cells.
Microchimerism is the presence of donor cells (<1% of all circulating recipient cells) in the recipient body. This phenomenon can occur from pregnancy, blood transfusion, and previous transplants. In liver transplants up to 20% of the recipients develop spontaneous operational tolerance. This can be due to large number of donor leukocytes that come with the transplanted liver and lead to microchimerism in the recipient.
Transplantation between identical monozygotic twins associated with marked tolerance. While, between dizygotic (HLA non-identical) twins, the microchimerism is incomplete and this cause incomplete tolerance. Tolerogenic strategies
Many protocols have been developed, with an aim to inducing tolerance in kidney transplant recipients. Thereby the immunosuppression can be discontinued.
Cellular therapy to achieve such tolerance are many:
· Total lymphoid elimination protocol includes irradiation of the LN, spleen, and thymus. It has high toxicity. Used in patient with multiple myeloma and co-existing ESRD.
· Splenectomy: splenic irradiation or splenectomy results in elimination of B lymphocytes and Ig M antibodies result in tolerance with immunosuppression. This regime result in graft survival rate exceeding 90% at 5 years.
· Multiple receptor ligand interactions blockade induces transplant tolerance by activation of T cell energy.
· Costimulatory pathways CD 28 receptor that bind to CD80 and CD86 ligands expressed on Ag-presenting cell.
There are new developing strategies in development from these are: regulatory T cell, dendritic cells, and others
Successful protocols with the aim of inducing tolerance in kidney transplant recipients enabling immunosuppression to be discontinued are listed as follows: Protocols achieving full donor chimerism Protocol achieving transient mixed chimerism Protocol achieving sustained mixed chimerism
Ben Lomatayo
3 years ago
Tolerance is the ability of the transplanted tissue or organ to stay alive with the host in absence of immunosuppression. Therefore it should show no signs of rejection on histology and no signs of immunologic reaction mounted against it. a lots of work have been done to achieve tolerance but still we are lagging behind and we still dreaming about it.
Ben Lomatayo
3 years ago
Tolerance originate from Latin ward tolero i.e to endure(1). Tolerance is co-existence of foreign organ in the host without the need foe immunosuppression. Clinical operational tolerance is where graft survives with histological features of rejection in absence of immunosuppression(3),(4). Immunological tolerance means no immune reaction directed to allograft in absence of immunosuppression .During development of lymphocytes in the thymus ,they learn how to differentiate self from non-self antigens. Central tolerance is when autoreactive T and B cells are cleared by clonal deletion in the thymus. Peripheral tolerance is elimination of the autoreactive T and B cells which bypasses central tolerance mechanism and researches systemic circulation. The mechanisms are deletion, apoptosis, energy and regulation or suppression(8 – 10). Regulatory T cell( thymus and peripheral) are important mediators of the immune tolerance( immune modulatory functions).
Tolerance signatures ; Lechler et al.(17) demonstrated ; expansion of peripheral and B and NK cells, less activated CD4 T cells, absence of donor specific antibodies, high numbers of FOXP3 , donor specific hyporesponsiveness of CD4 cells
Chimerism ; Situation where donor and host haematopoietic stem cells are staying together without immunologic response mounted against the donor cell. If little of donor cells remains( <1%) in the recipient is called Micro-chimerism. Examples are Blood Tx, Previous Tx, and Pregnancy
Tolerogenic Strategies :
Cellular therapies ; e.g. T cell depletion( ATG, Alemtuzumab, Basiliximab, Aldesleukin+ Rapamycin, Rituximab, Belimumab). Costimulation blockade( Abatacept, Belatacept, and Efalizumab). B cell therapy( Atacicept, Bortezomib)
Total lymphoid elimination protocols ; This protocol uses irradiation, and is more toxic therapy. The only indication is Multiple Myeloma+ ESRD
Splenectomy; The idea is get rid of circulating antibodies. This technique is popular in Japan for ABO incompatible transplant. However current literature demonstrated the role of spleen in induction and maintenance of regulator CD4 T cell, and there fore induces self tolerance. Other therapies are in the stages of development
Successful Protocols with the aim of inducing tolerance in kidney transplant allowing immunosuppression to be withdrawn ;
Full donor chimerism ; e.g. Massachusetts General Hospital(MGH) = non- myeloablative conditioning with T cell modulation +/- co-stimulation blockade and short term immunosuppression , Northwestern protocol
Transient mixed chimerism protocol ; MGH , combined kidney and bone marrow transplant plus immunosuppression withdrawal on board
Sustained mixed chimerism protocols ; e.g. Stanford protocol = conditioning therapy with total lymphoid irradiation + ATG
Facilitating cell infusion therapy (FCRx) and Macro-chimerism ; FCRx enhances transplantation of the haematopietic stem cells without risk of GVHD (27). Leventhal et al., showed durable whole blood macro-chimerism using FCRx in kidney transplant recipients(16)
CONCLUSION ; Tolerance is still our dream in transplantation science. partial tolerance has been reported in renal transplantation in the setting of non-adherance. The suggested protocols for induction of tolerance is hampered by the highly toxic regiments. Despite all these obstacle people are still working very hard to study more and more about the biology of tolerance.
Assafi Mohammed
3 years ago
TOLERANCE MEAN THAT THE BODY DEAL WITH THE EXISTING FOREIGN ANTIGEN WITHOUT DISPLAYING ANY SIGNIFICANT IMMUNE REPONSE.
ACCOMODATION MEAN THAT THE BODY DISPLAYS LESS SIGNIFICANT IMMUNE RESPONSE TO EXISTING FOREIGN ANTIGEN ,BUT OVERALL NO SIGNIFICANT INJURY.
Assafi Mohammed
3 years ago
SUMMARY OF THE ARTICLE
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression. It can be described as donor specific non-reactivity in experimental models .
Clinical operational toleranceis described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections. Immunological tolerance is no detectable immune reaction towards the allograft in absence of immunosuppression.
In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens.
Self-tolerance comprises of central and peripheral tolerance and can be described as a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones
Central tolerance
Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
In the thymus, T cells undergo a process of rearrangement, where they are incorporated with a receptor (TCR) and process of upregulation of CD4 and CD8 antigens takes place. As the cell matures, it has CD4 and CD8 antigens and is called double positive cell or thymocyte.
Double positive T cells start reacting with peptides in thymic stroma that represent the ‘self’ peripheral proteins. T cells that react too strongly with self-peptides are eliminated by apoptosis or subsequent negative selection. Those cells that interact favorably with self-peptides are in turn positively selected and eventually become mature T cells that express either CD4 or CD8 receptor (single positive T cells). This process is referred to as clonal selection.
Eventually, only 3-5% of original T cells that entered the thymus are positively selected and end up as mature T cells leaving the thymus.
B cells are also tested for reactivity to self-antigens before they enter the periphery. Immature B cells, developing in the bone marrow, test antigen through the B cell receptor (BCR).
Mechanism of central tolerance:
Step 1: Anergy-If signalling through the BCR is sufficiently weak, immature B cells can be rendered permanently unresponsive.
Step 2: Deletion- If immature B cells are strongly self-reactive, they are deleted.
Step 3: Receptor editing- Through BCR gene rearrangements, a new receptor with altered specificity is generated
Peripheral tolerance
Peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression.
Thymus-derived regulatory T (tTreg) cells are considered main mediators of central immune tolerance, whereas peripherally derived regulatory T (pTreg) cells function to regulate peripheral immune tolerance. A third type of Treg cells, termed iTreg, represents only the in vitro-induced Treg cells.
Mechanism of peripheral tolerance:
Deletion and apoptosis: This is also termed activation-induced cell death (AICD) and is mediated by interaction of Fas (CD95) with its ligand (Fas-L or CD95L) on T cells, and can occur in developing thymocytes as well as mature T cells.
Anergy: This is a state of hyporesponsiveness of T or B cells to further antigenic stimulation. It can result from antigenic stimulation in the absence of costimulation.
Regulation or suppression:Regulatory T cells (Treg cells) comprise of “natural” Treg cells and “adaptive” Treg cells. They control the type and magnitude of a given immune response to a foreign antigen, ensuring that the host remains undamaged.
Tolerance signatures (tolerance biomarkers)
Tolerant patients showed the following characteristics according to Lechler et al. In 2010:
expansion of peripheral blood B and NK lymphocytes.
fewer activated CD4+ T cells
lack of donor specific antibodies.
donor specific hyporesponsiveness of CD4+ T cells.
high ratio of FoxP3 to α-1,2 mannosidase gene expression.
differential expression of B cell related genes and associated molecular pathways .
Chimerism
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance. However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance.
Microchimerism is persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. Presence of such microchimerism can occur from pregnancy, blood transfusion and previous transplants.
Microchimerism leading to spontaneous operational tolerance has been seen in up to 20% of liver transplants thought to be due to large number of donor leukocytes that come with the transplanted liver and lead to donor microchimerism in the recipient.
Tolerogenic strategies
1.Cellular therapies: Potential impact of cellular therapies (Transplant Research Immunology group) has been extensively investigated by Wood K et al. 2.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.
3.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 transplants.
Different cellular therapies and it’s mechanism of actions :
1.T cell depletion:
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.
Alemtuzumab:Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes.
2. Costimulation blockade:
Blockade of CD28:CD80/86 costimulatory pathway: Abatacept & Belatacept.
Blockade of LFA-1:ICAM-1 co-stimulatory pathway: Efalizumab.
3.Other T cell therapies:
Basiliximab: Blockade of CD25
Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and stabilise the expression of FoxP3.
4.B cell therapies:
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. Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand) Bortezomib:Proteosome inhibitor causing apoptosis of mature plasma cells Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies in development:
1.Mixed chimerism; Infusion of donor bone marrow into myoablated /immune-condition ed recipient for producing co-existence of donor and recipient cells.
2.Regulatory T cells: Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production, down-regulate costimulatory and adhesion molecules, promote anergy and cell death, convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL- 10,TGF-B and IL35
3.Dendritic cells: Deletion of T cells, induction of Tregs and anergic T cells, expression of immunomodulatory molecules and immunosuppressive factors
4.Macrophages: Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and casp ase dependent depletion of activated T cells.
5.Myeloid derived suppressor cell: Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-Y producing T cells.
6.Mesenchymal stromal cells:Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T cells and downregulation of MHC Class II and co- stimulatory molecules
7.Regulatory B cells: Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM, expression of Fas-L .
Successful protocols with the aim of inducing tolerance in kidney transplant recipients enabling immunosuppression to be discontinued are listed as follows: Protocols achieving full donor chimerism:
Massachusetts General Hospital protocol (MGH): using HLA matched related donor kidney and bone marrow transplant for haematologic malignancy. 50% achieved removal of IS (5 out of 10), 30% achieved sustained anti-tumour response.
Massachusetts General Hospital protocol (MGH): using Haploidentical donor kidney and bone marrow transplant for haematologic malignancy. 75% in remission (3 out of 4) 2 likely tolerant.
Northwestern protocol: using Haploidentical/mismatched related and unrelated donor kidney and bone marrow transplant for ESRD without malignancy. 63% achieved removal of IS (5 out of 8).
Protocol achieving transient mixed chimerism:
Massachusetts General Hospital protocol (MGH): using Haploidentical donor kidney and bone marrow transplant for ESRD without malignancy. 4 out of 10 (40%) achieved sustained tolerance.
Protocol achieving sustained mixed chimerism:
Stanford Protocol: using HLA matched and haploidentical related and unrelated donor kidney and bone marrow transplant for ESRD without malignancy. 44% achieved removal of IS (HLA matched) 0% sustained tolerance (haploidentical or unrelated donor).
Ban Mezher
3 years ago
Tolerance is the ability of the immune system of recipient to recognize the donor organ as self antigen without using immunosuppressive .
Clinical operational tolerance functioning graft without histological features of rejection for at least one year without immunosuppression in otherwise immunocompetent person that can react normally to infection.
Immunological tolerance mean there is no serological immune response to graft in absence of immunosuppression.
Self tolerance is the ability of T & B cells recognize between self & non self antigen during their maturation in thymus & bone marrow. it include central & peripheral tolerance.
Central tolerance refer to destruction of reactive T & B cells by clonal deletion while peripheral tolerance refer to destruction of reactive T &B cells that escaped the central tolerance & present in peripheral circulation ( destruction by deletion & apoptosis, energy, regulation or suppression).
Chimerism is the presence of both recipient & donor hematopoietic stem cells inside the host without activation of immune response against donor cells. Micro chimerism is the presence of small number of donor cells in recipient circulation secondary to pregnancy, blood transfusion & previous transplantation.
There are different strategies to induce tolerance as:
cellular therapy by T & B cells depletion & co stimulation blockade.
total lymphoid elimination as irradiation of lymph nodes, spleen & thymus.
splenectomy
Several successful protocols used to induce tolerance in renal transplant including:
protocol to achieve full donor chimerism
protocol to achieve transient mixed chimerism
protocol to achieve sustained mixed chimerism
AMAL Anan
3 years ago
Tolerant patients showed the following characteristics
1-expansion of peripheral blood B and NK lymphocytes
2-fewer activated CD4+ T cells.
3-lack of donor specific antibodies.
4- donor specific hyporesponsiveness of CD4+ T cells.
5-high ratio of FoxP3 to α-1,2 mannosidase gene
expression.
6-differential expression of B cell related genes and associated molecular pathways.
Mangement to achieve tolerance.
**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.
** Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance.
AMAL Anan
3 years ago
Tolerance In Transplantation:
*Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
*Clinical operational tolerance: is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
* Immunological tolerance is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
* Self tolerance includes central and peripheral tolerance .
* Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
* peripheral tolerance controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression .
* Tolerance signature is for identifying those recipients that will achieve tolerance with minimal or no immunosuppression long term.
* Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cell.
* Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance . However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance .
*Tolerogenic strategies:
-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 treatment.
-Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance. But has clinical limitations as that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for
self-tolerance.
Reem Younis
3 years ago
Tolerance in Transplantation Tolerance is the ability of foreign tissue or organ to survive in the host without immunosuppression. Clinical operational tolerance is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infection. Immunological tolerance is no detectable immune reaction toward the allograft in absence of immunosuppression. Self-tolerance
The lymphoid system consists of T and B lymphocytes which are undergoing eduction and maturation in central lymphoid organs (thymus and bone marrow) and during this process T and B, cells learn to differentiate between self-antigens and non-self antigens. Central tolerance
It is the most important process by which potential autoreactive T and B cells are eliminated by a process called a clonal deletion. Peripheral tolerance
It sweeper mechanism of destroying that self-reactive T and B cells which somehow escaped the central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy and regulation, or suppression. Tolerance signature
Immunosuppression may affect tolerance signatures Immunosuppression may affect ‘Tolerance signatures’ and biomarkers may be different in those with established tolerance as compared to those on immunosuppression. In 2010 Lechler et al study, tolerant patients showed the following characteristics :
1. expansion of peripheral blood B and NK lymphocyte
2. fewer activated CD4 T cells
3. Lack of donor-specific antibodies.
4. donor-specific hyporesponsiveness of CD4 T cell.
5. the high ratio of foxP3to α1,2mannosidase gene expression
6. the differential expression of B cell-related genes and associated molecular pathways. Chimerism
It is the co-existence of donor and host hematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Transplantation between genetically identical monozygotic twin has shown the remarkable result of tolerance but among dizygotic twin, the microchimerism is incomplete and lead to inadequate tolerance.
Microchimerism is the persistence of a small number of donor cells( 1%of all circulating recipient cells) within the recipient body occur from pregnancy, blood transfusion, and previous transplantation. Tolerogenic strategies : Total lymphoid elimination protocol :This is achieved by irradiating the lymph nodes, spleen, and thymus. Clinical application is limited due to the high toxicity of this kind of treatment. Splenectomy: Splenic irradiation results in the elimination of B lymphocytes and IgM that result in a state of tolerance.
Splenectomy with other immunosuppressive regimens resulted in a graft survival rate exceeding 90% at 5 years according to a Japanese study.
The clinical limitation of splenectomy, studies have shown that the spleen is important for induction and maintenance of regulator CD4 CD25 T cells which are important for self-tolerance. Strategy T cell depletion: 1. ATG: it depletes T –cell blood and peripheral lymphoid tissues.
2.Alemtuzumab: it depletes monoclonal antibody to CD52 on T, B, NK. Costimulation blockade:
1.Abatacept, belatacept: Blockade of CD28:CD80/86 co-stimulatory pathway. 2.Efalizumab: ICAM-1 co-stimulatory pathway blockade. Other T cell therapies: 1.Basiliximab: Blockade of CD25.
2.Aldesleukin+Rapamycin: They increase T cell proliferation and survival, and stabilize the expression of FoxP3. B cell therapies: 1.Rituximab: it depletes monoclonal antibodies to CD20. 2..Belimumab: it blocks BAFF B activation. 3.Atacicept: it blocks BAFF and APRIL. 4.Bortezomib: It proteasome inhibitor. 5.Eculizumab: it blocks complement protein C5.
Mohamed Essmat
3 years ago
*Tolerance is the ability of the foreign organ to survive in the body of recipient without any immunosuppression without increased risk for infections .
*Clinical operational tolerance entails a well-functioning allograft in the absence of histological evidence of rejection without immunosuppression in an immunocompetent recipient for at least 1 year .
*Central tolerance is by which autoreactive T-cells and B-cells by clonal deletion are eliminated.
*Peripheral tolerance is a sweeping mechanism for elimination of self-reactive B and T cells which escaped central tolerance.
*Tolerogenic strategies consist of cellular therapies total lymphoid elimination protocols with irradiation of thymus, spleen and lymph nodes, and blocking of costimulatory pathways, Belatacept.
*Microchimerism is the presence of a small number of donor cell within the recipient body without inducing immunological reaction.
*A good instance of tolerogenic protocol that uses stem cell infusion to achieve a state of mixed chimerism.
Last edited 3 years ago by Mohamed Essmat
Hamdy Hegazy
3 years ago
A tissue or organ surviving in a foreign host without immunosuppression defines tolerance.
A well-functioning graft without histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host defines Clinical Operational tolerance.
lack of immune reaction towards the allo-graft in absence of immunosuppression defines Immunological tolerance which means that the allo-graft is accepted by the immune system.
Self-tolerance means that our immune system can recognize self from non-self-tissue and subsequently prevent harmful autoreactive lymphocytes.
Elimination of potentially auto reactive lymphocytes via clonal deletion defines central tolerance.
Thymocytes (double positive cells) are the mature T-cells after incorporating the CD4 and CD8 antigens in addition to T-cell receptor.
These Thymocytes react with the self peripheral proteins which are represented as peptides in the thymic stroma.
Cells that react strongly will be removed by apoptosis, process called negative selection.the favourably reacting cells become mature T-cells that express either CD4 or CD8 receptor (single positive T cell)—–à Clonal Selection process.
3-5% of the original T-cells are positively selected and leave the thymus gland as a mature T-cells.
B-cells will have maturation in the bone marrow via the B cell receptor.
Self reactive T-cells and B-cells that escaped central tolerance into the peripheral circulation will be destroyed by on of the following mechanisms:
Deletion and Apoptosis: AICD
Anergy: Hyporesponsiveness of Tor B-cells.
Regulation or Suppression: natural and adaptive T-reg cells
Thymus derived T-reg –à central immune tolerance.
Peripherally derived T-reg—–àperipheral immune tolerance.
In vitro induced T-reg cells.
Chimerism: Co-existence of donor and host hematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Microchimerism means persistence of a small number of donor cells within the recipient body which can lead to spontaneous operational tolerance in 20 % of liver transplant.
Tolerogenic strategies:
A- Cellular Therapies.
B- Total Lymphoid elimination protocols.
C- Splenectomy. Cellular therapies in use to induce tolerance:
1- T-cell depletion: using ATG, Alemtuzumab.
2- Co-stimulation blockade: using Abatacept, belatacept or Efalizumab.
3- Other T-cell therapies: Bailiximab, Aldesleukin+Rapamycin.
4- B-cell therapies: Rituximab, Belimumab, Atacicept, Bortezomib, Eculizumab. Total Lymphoid elimination protocol: Irradiating lymph nodes, spleen, and thymus. Limited to use in patients with MM and ESRD to induce a state of lympho-hematopoietic chimerism. Splenectomy: was used in Japan for ABO incompatible transplants because spleen produces B-lymphocytes and IgM
The available protocols for inducing tolerance have significant drawbacks in terms of drug toxicity and unpredictable results
Tahani Hadi
3 years ago
Tolerance means well functioning allograft in the absence of exogenous immunosuppression and having intact immune system it’s achieved by controlling T cells reactivity in both central and peripheral .
Partial tolerance also used to describe that when the recipient is using minimal dose of immunosuppression after induction using alemtuzumab.
Central tolerance means eliminating T cells reactivity against Ag (donor Ag) through thymus which will cause deleted of developing T cells coronal deletion ,reaching a state that both donor and recipient cells are present (chimerism) but this need active healthy thymus
Peripheral tolerance by using self tolerance T cells that are escaped from central tolerance will be detected and deleted by peripheral tolerance through various mechanisms
Nasrin Esfandiar
3 years ago
Outcome of transplantation has improved in recent years using patient immunosuppression medications. Immunosuppressant drugs have adverse effects such as infections or malignancy. So, the ultimate goal in transplantation is tolerance. It means survival of a donor organ in recipient’s body with no immunosuppression. Self-tolerance means no attack to self-antigens. That is achieved by central tolerance and peripheral tolerance. Central tolerance happens in thymus during T-cell development and is done by clonal deletion, anergy or receptor-edition. But some of auto reaction T cell can still be present in the periphery and are handled by peripheral tolerance. In addition to T REG and B REG cells, anergy and apoptosis are different mechanisms of peripheral tolerance. T REG cells are usually CD4+, CD25+ and FOXP3positive.A subset of T reg cells are CD4+, FOXP3- type1 regulatory T (Tr1) cells that have immunomodulatory effects which attracts attention. Different tolerance signatures or biomarkers are identified. Robello-Mesa et al.validated a gene expression signature and Brouard et al. Identified a score based on six genes and two demographic variable that was associated with de novo DSA. Multicenter study conducted by Lechler et al.in 71 KT patients with sex and age matched control showed five characteristics of tolerant persons.
Microchimersim means presence of a few donor cell with in the recipient circulation. Chimerism means presence of donor and recipient’s stem cells without a reaction. Different tolerance inducing strategies are tried including cell therapies, lymphoid elimination protocols, costimulatory signal blockage and even splenectomy. Tolerance protocols at MGH and Stanford used mixed chimerism strategies whereas protocols at Johns Hopkins and Northweetaren utilize full-chimerism strategies.
Dalia Ali
3 years ago
Transplantation tolerance is a state in which the immune system of the recipient of a tissue or
organ transplantation does not attack the
transplanted tissue. Transplantation tolerance is induced by immunosuppression, and prevents rejection of the transplant.
Clinical operational tolerance” is described as a well-functioning graft with out histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other problems including infections
Immunological tolerance” is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specifi c immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
Self-tolerance refers to the ability of the immune system to recognize—and therefore not respond against—self-produced antigens. If the immune system loses this ability, the body can start to attack its own cells, which may cause an autoimmune disease
central tolerance in the thymus and peripheral tolerance in extrathymic lymphoid tissue
Microchimerism is persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. can occur from pregnancy, blood transfusion and previous transplants.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerogenic strategies
1-Cellular therapies:
2-Total lymphoid elimination protocols
3-Splenectomy
Current tolerogenic strategies in use.
*Strategy T cell depletion ATG: T-cell depletion in blood and peripheral lymphoid tissues
and Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
*Costimulation blockade Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
*Other T cell therapies Basiliximab: Blockade of CD25
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 cell therapies
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Tolerance is important goal because transplant recipients are subjected to global immunosuppression that leaves them at increased risk for infections and malignancies. In addition, current chronic immunosuppression regimens do not guarantee indefinite or even excellent long-term allograft
Ahmed Faisal
3 years ago
☆ Tolerance us presence of foreign organ in a host with no need of immunosuppression.
Clinical operational tolerance is no histological finding of rejection of well-performed graft in an immunocompetent host without need of immunosuppressive for a year at least.
Immunological tolerance is no immune responses against allograft without immunosuppressives. The immune system of host accepts the graft in non-appearance of immunosuppression.
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☆ Self-tolerance
It is a type of monitoring system to kill and stop any expansion of harmful T and B cells.
It is consist of central and peripheral tolerance.
T and B lymphocytes mature in the thymus and bone marrow where they learn to differentiate between self-antigen and non-self antigen.
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☆ Central tolerance
It is elimination of potentially auto-reactive T and B cells by clonal deletion.
Mechanism: angery, deletion or receptor editing.
T cells reach the thymus to mature. They are called double negative as they lack CD4 and CD8. During maturation, they have CD4 and CD8 so are called double positive thymocytes.
• Negative selection is elimination of T cells which react strongly with self-peptides.
• Colnal selection is maturation of single positive T cells which react with self-peptides and express either CD4 or CD8.
T cells are tested for reactivity before leaving the thymus. Positive selection and maturation of T cells occur to only 3-5 % of original T cells.
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☆ Peripheral tolerance
Sweeping system that destroys the self-reactive T and B cells in peripheral circulation as they are not damaged by central tolerance mechanism.
Mechanism: deletion and apoptosis, angery and regulation or suppression.
Tr1 cells are subtype of pTreg cell and have immunomodulatory functions ,so they are target for tolerance.
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☆ Tolerance signatures
Spontaneous tolerance, which was first reported in 1975, was achieved by chance in non-adherant patients.
Thera are biomarkers for tolerance signature and several studies showed that tolerant patients have the same findings such as:
• lack of DSA.
• fewer activated CD4+ Tcells.
• expansion of peripheral blood B lymphocytes.
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☆ Chimerism
The host accepts donor haematopoitic stem cells without stimulating immunological system against the donor cells.
Exposure to foreign antigens in uteto may lead to microchimerism and therefore acquired tolerance.(Owen et al 1945)
Microchimerism is presence of donor cells within the recipient (< 1% of all circulating recipient cells). It developes due to pregnancy, previous blood transfusion or transplantation. It leads to spontaneous operational tolerance.
Dizygotic twins (HLA non-identical) show incomplete microchimerism and therefore inadequate tolerance.
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☆ Tolerogenic strategies
• Current tolerogenic strategies in use
ATG, Alemtuzmab, Abatacept, Basilixmab,
Rituximab, Bortezomib,and Eculizumab.
• Current cellular therapies in development
Mixed chimerism, Regulatory T cell,
Regulatory B cells and myeloid derived
suppressor cell.
• Total lymphoid elimination protocol
Irradiation of LNs, spleen and thymus.
Limited use in clinical practice.
Used in multiple myeloma with ESRD.
• Splenectomy
Results in elimination of B lymphocytes and
IgM and leads to tolerance
Used in Japan in ABO incompatible
transplantation resulting in higher rate of
graft survival.
Other studies show that spleen is essential
for self- tolerance through maintenance of
regulatory T cells.
There are many successful protocols aiming to achieving tolerance in kidney transplantation and stoppage of immunosuppressive theray through full chimerism , transient or permanent mixed chimerism.
Rathore R, Gunawansa N, Sharma A, Halawa A (2017) Current State of Tolerance: The Holy Grail. Arch Clin Nephrol 3(2): 057-063. DOI: http://dx.doi.org/10.17352/acn.000028
Theepa Mariamutu
3 years ago
Summary of Tolerance
-ability of foreign tissue or organ to survive in host without immunosuppression
-Clinical operations tolerance – functioning graft without histological evidence of rejection in the absence of IS for at least 1 year in immunocompetent host capable of responding to lather challenges including infections
-immunological tolerance – no detectable immune reaction towards allograft in the absence of IS.
Self tolerance
-lymphoid system comprises T and B lymphocytes which controls the immunity protecting the host from foreign pathogens
-T cell and B cell undergo education and maturation proceed in the central lymphoid organs
Central Tolerance
-affinity-avidity model- self tolerance divided into central and peripheral tolerance – prevent expansion of potential harmful auto-reactive T and B cell clones
-intermediate affinity – self reactive T cells with intermediate affinity / avidity for self antigens that escape thymic negative selection and released into periphery, display lower affinity for MHC/self peptide complexes but capable of self peptide driven profile ration and may differentiate into effector cells
-central tolerance is most important -clonal deletion, eliminate auto-reactive T and B cell
-T and B cell mature in thymus and BM
-T cells first reach the thymus – immature and lack of TCR and lack of CD4 /CD8 antigens (double negative)
-TCR incorporated and uporegulation of CD4/8 antigens in thymus
-double positive cells – starts ewcting to self peripheral proteins in thymic stroma
-self peptides that strongly react with T cell – eliminated by apoptosis ( negative selection)
-cells that react favourably will mature either CD4/CD8- clonal selection
-thymocytes with low affinity -die within thymus
-B cells -immature -in bone marrow through the B cell receptor
Peripheral Tolerance
-destroying self reactive T and B cells that escaped central tolerance mechanism and circulating in peripheral
-controlled by one of process: deletion, apoptosis, energy and regulation or suppression
-tTreg – main mediators of central immune tolerance
-pTreg – regulate peripheral immune tolerance
-iTreg – in vitro induced Treg cells
Mechanism of central tolerance
Step 1: Anergy- If signalling through the BCR is sufficiently weak, immature B cells becomes unresponsive forever
Step 2: Deletion- If immature B cells are strongly self-reactive -deleted
Step 3: Receptor editing- Through BCR gene rearrangements, a new receptor with altered specificity is generated
Mechanism of peripheral tolerance
Deletion and apoptosis/activation-induced cell death (AICD): mediated by interaction of Fas (CD95) with its ligand (Fas-L or CD95L) on T cells
– can occur in developing thymocytes as well as mature T cells.
Anergy: state of hyporesponsiveness of T or B cells to antigenic stimulation. Can be result from antigenic stimulation in the absence of costimulation.
Regulation or suppression: Treg cells consists of “natural” Treg and “adaptive” Treg. They control immune response to a foreign antigen whilst ensuring that the host remains undamaged
Foxp3, pTreg and iTreg expressed in cells depends on stably-divided into 2 subsets
-Calssical CD3+Foxp3+Treg
-CD4+Foxp3-type 1 regulatory T (Tr1) cells – have been recognised for immunomodulatory
Functions – make a them promising target for prevention of organ transplant rejection
Tolerance signatures
-help in formulating predictive models for identifying those recipient that will achieve tolerance with minimal or IS free in long run
Tolerant patients showed the following characteristics
• expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of donor specific antibodies
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene
expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism
Chimerism – co-existence of donor and host haematopoietic stem cells inside the host without stimulating immunological reaction against donor cells
Transplantation between genetically identical monozygotic twins – shown results of tolerance
-Dizygotic twins- microchimerism -leads to inadequate tolerance
Microchimerism – persistence of <1% of all circulating recipient cells within the recipient body c
-occur from pregnancy, blood transfusion and previous transplants.
Mechanism of action
• 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
• Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
Costimulation blockade
• Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
• Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
Other T cell therapies
• Basiliximab: Blockade of CD25
• Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and stabilise the expression of FoxP3
B cell therapies
• Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand)
• Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
• Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies still in research
Mixed chimerism
Infusion of donor bone marrow into myoablated /immune-conditioned recipient for producing co-existence of donor and recipient cells
Regulatory T cells
Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production, down-regulate costimulatory and adhesion molecules, promote anergy and cell death, convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL- 10,TGF-B and IL35
Dendritic cells
Deletion of T cells, induction of Tregs and anergic T cells, expression of immunomodulatory molecules and immunosuppressive factors
Macrophages
Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and casp ase dependent depletion of activated T cells
Myeloid derived suppressor cell
Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-Y producing T cells
Mesenchymal stromal cells
Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T cells and downregulation of MHC Class II and co- stimulatory molecules
Regulatory B cells
Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM, expression of Fas-L
Tolerance is the dream of every doctor in the transplantation team. simply it defined as graft survival without immunosuppression with no rejection.
Central tolerance for T lymphocytes is done in the thymus where autoreactive T cell is eliminated by process called negative selection. Peripheral tolerance in which peripheral derived T lymphocytes can suppress the inflammation.
Tolerance signatures is an important subject , and Knowing which from our patients developed graft tolerance is of critical importance to allow reduction of immunosuppressive drugs. Till now no single marker had been agreed as marker of tolerance, several markers had been suggested but still as experimental markers.
Chimerism is the presence of hematopoietic stem cells from the donor and recipient without occurrence of graft rejection. in this way we can induce tolerance for the graft. it used in many protocols to induce tolerance.
Strategies to induce tolerance :
Cellular strategies: This strategies uses hematopoietic stem cell from the donor to induce tolerance . Various protocols had been suggested with different conditioning regimes with different results . One strategy called Facilitated Cell Infusion had good results.
Total lymphoid irradiation strategy: it uses irradiation of the spleen, thymus and lymph nodes . this strategy had high level of toxicity, and it’s use is limited to certain patients with multiple myeloma and renal failure.
Spleenectomy : By removing the spleen we can remove a major site of antibody production , and some centers use it for ABO incompatible donors . Some critized this strategy because spleen is also a site of regulatory T cells which are important in tolerance.
Another strategy to induce tolerance is to use various drugs to inhibit T cells and B cells , some of these drugs are in use in clinical practice. These drugs like ATG, Belatacept, Basiliximab, Rituximab ,Bortezomib, Belimumab and Atacicept.
Professor Ahmed Halawa
Admin
3 years ago
One last question Have we achieved tolerance or near tolerance (transplantation survived on minimal immunosuppression)?
Not really prof although partial tolerance have been reported in setting of non-adherence in renal transplantation. some success in animal models but in human not yet.
Mohamed Fouad
3 years ago
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
Clinical operational tolerance is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
Immunological tolerance is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
T cells and B cells undergo education and maturation in the central lymphoid organs. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens.
self-tolerance comprises of central and peripheral tolerance and can be described as a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones.
Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
Peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that in some way escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells. Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance.
Microchimerism is persistence of a small number of donor cells within the recipient body, this can occur in pregnancy, blood transfusion and previous transplant.
Strategies to induce Tolerance
Total lymphoid elimination protocols: by irradiating the lymph nodes, spleen and thymus. 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.
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 transplants. some recent studies have shown that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance.
ATG: T-cell depletion in blood and peripheral lymphoid tissues
Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes.
Costimulation blockade: Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway.
Basiliximab: Blockade of CD25 Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival
B cell therapies Rituximab: Depleting monoclonal antibody to CD20 Belimumab: Blockade of BAFF B cell activating factor causing depletion of follicular and alloreactive B cells. Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
Eculizumab: a long-acting humanized monoclonal antibody targeted againstIt inhibits the cleavage of C5 into C5a and C5b and hence inhibits deployment of the terminal complement system including the formation of MAC.
I will quote this paragraph from your answer” 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 transplants. some recent studies have shown that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance”
Mahmud Islam
3 years ago
Tolerance is the capability of a transplanted organ in our sense to survive in the host without immune suppression. this could be clinical showing good histological findings or immunological shown by no immune activity against donor’s organ.
t cells play a key role. after maturing and presenting cd4/cd8 positivity, the T cells that are not consistent with self are eliminated by negative clonal selection. cells that escape this central selection are swept peripherally. tolerance signatures drew attention since the 1970s. In 2010, Lechler et al. published their paper showing some characteristics of tolerant patients mainly with absent DSAs and fewer CD4+ cells. many tolerogenic strategies are applied. mainly ATG repletion of lymphocytes, monoclonal antibodies like belatacept and basiliximab in addition to B cell depletion by rituximab are used.
chimerism first studied in bone marrow transplantation is also studied and used for renal transplant patients especially in patients with malignancy with promising results. Massachusetts General Hospital protocol (MGH) had some protocols. either full sustained or transient full immune impression withdrawal was not attained except around 50 of cases (mean ). still, we need to understand the complex immune system. this is the big challenge
Tolerance is the ability of foreign tissue or organ to survive in a host without immunosuppression.
Self tolerance: the ability of B & T cells to differentiate between self and non self antigens.
Central tolerance: is the process by which the potentially autoreactive T & B cells are eliminated by clonal deletion.
Peripheral tolerance: the mechanism of destroying self reactive T & B cells that escape the central tolerance and end up in the peripheral circulation.
Chimerism: co-existence of donor and host hematopoietic stem cells inside the host without inducing immunological reaction against donor cells.
Microchimerism: the persistence of a small number of donor cells within the recipient body, this can occur in pregnancy, blood transfusion and previous transplant.
Tolerogenic strategies:
Cellular therapies: different cellular therapies in development, knowledge of their mechanisms of action is still under development
Total lymphoid elimination protocols: total irradiation of lymph nodes, spleen and thymus. clinical application is limited due to toxicity.
splenectomy: previously used for ABO incompatible transplantation.
Other T cells therapies: Basiliximab, Aldesleukin + Rapamycin
B cells therapies: Rituximab, Belimumab, Atacicept, Bortezomib, Eculizumab
Achieving tolerance in transplantation is still a challenge, the proposed protocols for inducing tolerance have significant complications due to drug toxicities and the unpredictable results. cellular therapies appear to be promising.
Regulatory T cells: infusion of expanded regulatory T cells
Dendritic cells: Deletion of T cells, induction of T regulatory cells & anergic T cells
Macrophages: depletion of activated T cells
myeloid derived suppressor cells
mesenchymal stromal cells
Regulatory B cells
Splenectomy:
stops production of B lymphocytes & IgM, used in ABO incompatible transplant
leads to high rate of graft survival
limited as recent studies showed that spleen is important for induction of regulatory T cells that are important for self tolerance
Total lymphoid elimination:
irradiation of lymph nodes, spleen & thymus
highly toxic
used only in multiple myeloma with end stage renal disease to induce lymphohematopoietic chimerism.
since transplantions started, our aim that the kidney graft not be rejected, and the recipent can tolerate or adapte with this foreign antigens.
types of toleance
a-Self tolerance is defined as the ability of B and T lymphocytes to maturate differentiating between self and foreign antigens therefore not attacking self antigens
b-Central tolerance a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion
c-peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression
stratiges to achive tolearnce in recipent
1- Total lymphoid irradiation ( thymus, lymph nodes, spleen) , high risk of infections.
2- Splenectomy in ABO incompatible donor, but spleen is important for regulatory T cells induction and maintenance
3- Costimulation blockade since activation of T Lymphocytes needs that one or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 suppress T cells, this lead to development of Belatacept (a high affenity variant CTLA4-Ig)
4- Donor stem cell infusions to develop chimerism between donor and recipient using short period of immunosuppression and co-stimulation blockade with excellent results
5- T cell directed therapy
a⦁ Basiliximab that block CD25
b⦁ Aldesleukin + Rapamycin that Increase proliferation of regulatory T cell
6- B cell directed therapy
a⦁ Rituximab that deplete CD20
b⦁ Belimumab that Block BAFF B cell activating factor causing alloreactive Bcell depletion
c⦁ Atacicept: Blockade of BAFF and APRIL (A proliferation inducing
ligand)
d⦁ Bortezomib that produce mature plasma cell apoprosis
e⦁ Eculizumab that block C5 to prevent formation opf MA
Tolerance is the ability of the foreign organ to survive in the body of recipient without any immunosuppression and it is the ultimate goal of managing transplantation without complication of immunosuppressive drugs such as infections and malignancies.
Clinical operational tolerance was described as well-functioning allograft in the absence of histologic evidence of rejection without immunosuppression for at least 1 year when the host is immunocompetent.
Immunological tolerance is defined as no detectable reaction toward allograft antigens in the lack of immunosuppression.
During maturation in lymphoid tissues, T and B cells learn to differentiate between self-antigens (self-tolerance) and non-self (foreign antigens).
Self-tolerance consists of central and peripheral tolerance. Central tolerance is the most important process by which autoreactive T-cells and B-cells by clonal deletion are eliminated. During the maturation process, in thymus, T cells undergo a rearrangement process and form double positive T cells (have both CD4 and CD8). Then if these cells react too strongly with self-peptides will be eliminated by apoptosis (negative selection) and those with favorable reaction with self-peptides undergo positive selection and form single positive T cells (have CD4 or CD8). The process of negative selection is true for B cells in bone marrow as well. Peripheral tolerance is a sweeping mechanism for elimination of self-reactive B and T cells which escaped central tolerance. Mechanisms of central tolerance are anergy, deletion and receptor editing; and the mechanisms of peripheral tolerance are deletion and apoptosis, anergy and regulation or suppression. Thymus Treg cells are considered the main mediators of central tolerance and peripheral Treg cells are the main regulators of peripheral immune tolerance. Tr1 cells are the promising target for the prevention of transplant rejection.
In one study, tolerant patients have special characteristic including: expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, lack of donor specific antibodies, donor specific hyporesponsiveness of CD4+ T cells, high ratio of FoxP3 to α-1,2 mannosidase gene expression, differential expression of B cell related genes and associated molecular pathways.
Microchimerism is the persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body without inducing immunological reaction that can lead to spontaneous operational tolerance as is seen in 20% of liver transplantation.
Tolerogenic strategies consist of cellular therapies (such as mixed chimerism, stem cell infusion, infusion of Treg and B reg cell, dendritic and macrophage cells, …), total lymphoid elimination protocols with irradiation of thymus, spleen and lymph nodes, splenectomy, and blocking of costimulatory pathways with different agents such as CTLA4Ig, Belatacept; which of them have special limitations and applications.
One of the best examples of tolerogenic protocol is MGH protocol that uses stem cell infusion to achieve a state of mixed chimerism. This protocol uses T cell modulation and co stimulation blockade with short term immunosuppression without myeloablation. This model is evident of central tolerance with excellent allograft survival.
Transplantation Tolerance :referes to the ability of the transplanted gragft to survive in the immunocompetant recipient without using immunesuppressive drugs (Immunogenic tolerance) and in Abecense of histological signs of rejection for 1 year at least (Clinical operational tolerance ). It was first described in expremental model in 1950 and since then ongoing efforts are exerted trying to identify biomarkers for tolerance that can be applied clinically to identify tolerant recipients , in whom the graft can survive with minimal immunesuppression .
Tolerant patients are characterized by 1- Absent of DSA 2- Increased number of prepheral blood B and NK cells 3- Few activated CD4+ T cells with hyporesposeviness to DSA 4- high ratio of FoxP3 to α-1,2 mannosidase gene expression 5- different expression of B cell related genes and molecular pathways
Chimerism, refres to presence of some of the donor heamatopiotic stem cells in the recipient without inducing immune response against these donor cells , representing a state acquired tolerance that results from exposure to non self antigens during early life or from blood transfusion , pregnancy and previous transplantation .
Therapeutic strategies aiming at achieving tolerance include
1- Elimination of the whole lymphoid tidssue through irradiating spleen , LNs and thymus . But this is associated with serious complications , thus it is only preserved for MM associated with ESRD.
2- Splenectomy or Splenic irradiation to eliminate B lymphocytes and IgM.
3- T cell depletion through either ATG or Alemtuzumab Or Blockage by Basiliximab
4- Blocking the costimulatory signals for T cell activation leading to T cell anergy via Abatacept, Belatacept , falizumab
5- B cell directed therapy as a- CD20 depleting monoclonal antibody as Rituximab b- depletion of follicular and allore active B cells via blocking BAFF B cell activating factor as Belimumab and Atacicept c- Proteosome inhibitor leading to apoptosis of mature plasma cell as Bortezomib d- Blocking complement activation via blocking of complement protein C5 as Eculizumab
Despite advances in organ transplantation with advances in immunosuppression , but still immunosuppression has major side effects mainly infections and malignancy that affects patients survival .
Understanding complicated and organized functions of immune system is the starting point to reach the goal of achieving clinical or operational tolerance long term in renal transplant recipients in the absence of immunosuppression .
Tolerance ; is the ability of a foreign tissue or organ to survive in a host without immunosuppression as the host can’t recognise the foreign orange as non self so it doesn’t initiate immunresponce to it and it’s describedas a state of donor specific non-reactivity.
Clinical operational tolerance ; is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
Immunological tolerance ;is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
Self-tolerance; in our early life with
development of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens this is done in 2 steps central and peripheral to ensure elimination of harmful auto-reactive T and B cell clones this process is called clonal deletion .
In the thymus T cells is incorporated with TCR
with upregulation of CD4 and CD8 on its surface and it’s called double positive TCells or thymocytes
which starts to react with thymic peptide representing self antigen are deleted by apoptosis
While 3-5 % of T cells that entered the thymus and had favourable reaction with self peptides become mature released with either CD4 or CD8 receptors and so called single positive T cells.
B cells are also tested for reactivity to self-antigens before they enter the periphery. Immature B cells, developing in the bone marrow, test antigen through the B cell receptor.
Peripheral tolerance
Some T and B cells can escape to peripheral circulation and can later become potentially pathogenic effector cells.
Peripheral tolerance; it is a mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression.
Thymus-derived regulatory T (tTreg) cells are considered main mediators of central immune tolerance, whereas peripherally derived regulatory T (pTreg) cells function to regulate peripheral immune tolerance. third type of Treg cells, termed iT reg, represents only the in vitro-induced T reg cells.
pTreg, and iT reg cells may be divided into two subsets:
* Classical CD4+Foxp3+ T reg cells and
* CD4+Foxp3− type 1 regulatory T (Tr1) cells.
Peripherally derived regulatory T ) cell subset (Treg CD4+Foxp3− type 1 regulatory T (Tr1) cells have immunomodulatory functions which may be promising in prevention of organ rejection.
The suppressive function of Tregs relies heavily on high and stable expression of the transcription factor FOXP3, which, together with other transcription factors, activates anti-inflammatory genes and represses proinflammatory genes.
transcription factor Foxp3 is critically important for the development and function of Tregs. Foxp3 not only can keep the cells on right developmental tracks toward a suppressive phenotype, but also seems to be a prerequisite to for stabilizing the Treg lineage . Furthermore, loss of Foxp3 expression over time impairs the suppressive activity of Tregs (1).
Tolerance signatures; it was found that some non transplanted patients are not adherant to immunosuppression and they didn’t reject the foreign oragan.
Tolerant patients showed the following characteristics :
• expansion of peripheral blood B and NK lymphocytes
•fewer activated CD4+ T cells
•lack of donor specific antibodies
•donor specific hyporesponsiveness of CD4+ T cells
•high ratio of FoxP3 to α-1,2 mannosidase gene expression
•differential expression of B cell related genes and associated molecular pathways
Chimerism
It’s the presence of both donor and host haematopoietic stem cells inside the host without causing immunological reaction against donor cells.
Microchimerism
It is the persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. Presence of such microchimerism can occur from pregnancy, blood transfusion and previous transplants.
Microchimerism leads to spontaneous operational tolerance has been seen in up to 20% of liver transplants thought to be due to large number of donor leukocytes that come with the transplanted liver and lead to donor microchimerism in the recipient.
Tolerogenic strategies ;
•Cellular therapy
Using different kinds of cells which may be doner bone marrow cells to induce chimirism ,T reg cell to modulate the immune response and produce Anergy , other types of cells sush as dentiritic , macrophages,regulatory B cells all are studied to modulate immune system and induce tolarance .
•Total lymphoid elimination protocols:
using irradiating the lymph nodes, spleen and thymus this highly toxic and not used in practice to all patients but can be limited to multiple myeloma patients and co-existing end stage renal failure to induce a state of lympho-haematopoietic chimerism.
•Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance but the main drawback is that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance.
There are some current strategies in use to achieve tolerance:
* T cell depletion with induction of T reg using ATG
* depleting monoclonal Ab to CD 52 on T ,B And NK cells and monocytes by Alemtuzumab
And basiliximab blocking of CD 25 .
* blocking co stimulation pathways using balatacept and abatacept.
* B cell therapy using rituximab monoclonal Ab to block CD 20 .
1 Fontenot JD, Gavin MA, Ruensky AY. Foxp3 programs the evelopment an function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4:330–6.
Tolerance is the survival of graft without using any immunosuppressive medicines.
It has many aspects: clinical one, denoting graft function without immunosuppressive and immunological one, referring to undetectable antibodies against donor antigens.
Selftolerance is a natural mechanism of differentiating between one own antigen and foreign ones.
Another important term is Chimersim denoting having both host and donor stem cells without evoking the immune system.
refers to a foreign tissue or organ’s ability to survive in a host without being immunosuppressed.
it can be described as donor-specific non-reactivity.
In the absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges such as infections, “clinical operational tolerance” is defined as a well-functioning graft with no histological evidence of rejection in the absence of immunosuppression.
Self-tolerance
T and B lymphocytes make up the lymphoid system, which regulates the immune system and protects the host from external diseases.
T cells and B cells are educated and matured in the key lymphoid organs, the thymus and bone marrow, throughout the lymphoid system’s developmental process. T and B lymphocytes learn to distinguish between self-antigens and non-self (foreign) antigens throughout this maturation phase.
Tolerance in the centre
Self-tolerance, which includes both central and peripheral tolerance in the affinity-avidity model, can be thought of as a kind of surveillance mechanism that prevents the spread of potentially harmful auto-reactive T and B cell clones.
Self-reactive T cells with intermediate affinity/avidity for self-antigens that survive thymic negative selection and are discharged into the periphery are referred to as intermediate affinity.
The most essential method by which potentially auto-reactive T and B cells are removed is central tolerance, which is achieved by a process known as clonal deletion.
Peripheral tolerance
is a cleaner mechanism that kills self-reactive T and B cells that have gotten past the central tolerance system and are now floating about in the bloodstream. They are regulated or suppressed by one of the following processes in the periphery: deletion and apoptosis, energy, and regulation or suppression.
CD4+Foxp3 type 1 regulatory T (Tr1) cells, a peripherally derived regulatory T (Treg) cell subgroup, have garnered growing attention for their immunomodulatory properties, making them a prospective target for organ transplant rejection prevention.
Sherif Yusuf
3 years ago
Definitions
⦁ Tolerance is surviving of foreign tissue or organ without immunosuppression
⦁ Immunological tolerance is the absence of immune response to a foreign tissue or organ
⦁ Clinical tolerance means that in an immunocompetent patient without immunosuppression for 1 y, the graft is clinically stable with no signs of rejection.
⦁ Self tolerance the ability to identify self antigens as self by T and B lymphocytes
⦁ Chimerism is the absence of immunological reaction between donor and recipient stem cells
⦁ Microchimerism is presence of few donor cells < 1% of recipient cells in the recipient circulation due to previous sensitization from pregnancy, previous transplant and blood transfusion
Mechanism of tolerance
Immature T lymphocytes lacking CD4, CD8 antigens (double negative) migrate to the thymus, acquire TCR , mature and acquire CD4, CD8 antigens (double positive), double positive cells which react aggressively with self antigens in thymic stroma are deleted (clonal deletion) by negative selection or apoptosis and those reacting well with self antigens are selected (clonal selection) to be mature cell (3-5% of total T cells) and express CD4 or CD8 receptors (single positive) in a process called clonal selection then leave the thymus
Immature B cells migrate to BM, cells which react aggressively with self antigens in BM are deleted and those reacting well with self antigens are selected and acquire BCR
The process of clonal deletion of self-reactive T and B cells is called central tolerance
Self reactive B or T cells can escape central tolerance and enter peripheral circulation, these cells can be eliminated by deletion and apoptosis, energy, and regulation or suppression (peripheral tolerance)
Central tolerance is regulated by thymus-derived regulatory T (tTreg) cells, while peripheral tolerance is regulated by peripherally derived regulatory T (pTreg) cells which are 2 types depending on whether the cell express Foxp3
– CD4 + Foxp3+ Treg cells
– CD4 + Foxp3 – type 1 regulatory T (Tr1) cells (may be a target for tolerance)
Criteria of tolerant patient (tolerance signature)
⦁ Increase in peripheral blood B and NK lymphocytes and decrease activated CD4+ T cells with hypo responsiveness to donor cells
⦁ Absence of DSA
⦁ Ratio of FoxP3 to α-1,2 mannosidase gene expression is high
⦁ Expression of B cell related genes
Strategies for induction of tolerance
1- Total lymphoid irradiation ( thymus, lymph nodes, spleen) in multiple myloma associated with ESRD, but there is very high risk of infection using this therapy
2- Splenectomy in ABO incompatible donor, but spleen is important for regulatory T cells induction and maintenance
3- Costimulation blockade since activation of T Lymphocytes needs that one or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 suppress T cells, this lead to development of Belatacept (a high affenity variant CTLA4-Ig)
4- Donor stem cell infusions to develop chimerism between donor and recipient using short period of immunosuppression and co-stimulation blockade with excellent results
5- T cell directed therapy
⦁ Basiliximab that block CD25
⦁ Aldesleukin + Rapamycin that Increase proliferation of regulatory T cell
6- B cell directed therapy
⦁ Rituximab that deplete CD20
⦁ Belimumab that Block BAFF B cell activating factor causing alloreactive Bcell depletion
⦁ Atacicept: Blockade of BAFF and APRIL (A proliferation inducing
⦁ ligand)
⦁ Bortezomib that produce mature plasma cell apoprosis
⦁ Eculizumab that block C5 to prevent formation opf MAC
What is meant by tolerance in your own words? Have we managed to achieve tolerance?
tolerance means body recognize renal allograft as self not non self , so no immunosuppression needed and no rejection attacks.
still reaching tolerance is under research.
Ala Ali
Admin
3 years ago
What are your thoughts about bone marrow and kidney transplantation for patients with multiple myeloma? Do you think this is a tolerogenic strategy? Have you ever heard about such trials?
As in the review (Published online 2016 Apr 30. DOI: 10.1155/2016/6471901
Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance written by : Yi-Bin Chen, Tatsuo Kawai, and Thomas R. Spitzer ) it was proposed to be of benefit to do BMT several months after Kidney Tx). It may have promise but I think we need to set the protocols before applying this risky procedures in otherwise healthy patients (namely who only need kidney tx).
I came across with middle-aged women but I could not remember the matching of her donor. she left all medications abruptly and came late to transplant center I visited 6 years ago and I was told she is one of about 50 (maybe 15) in the world. samples of her blood were sent to European research center. Still, we need research about tolerance and mechanisms of achievements to lower risk of unnecessary high doses of immune suppression
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerance could be achieved by irradiating central and peripheral lymphatic systems including lymph nodes, spleen and thymus. The high toxicity of this approach has limited it clinical use. However, patients with hematologic malignancies, and in particular patients with multiple myeloma and co-existing end stage renal failure, immunological tolerance to a renal allograft after having previously received a hematopoietic stem cell transplant from the same donor was attempted. But does is approach worth? In real life, continuous immunosuppression puts transplant recipients at risk of severe infections, malignancies, increased cardiovascular morbidity and mortality, and drug related side effects like de novo diabetes, dyslipidemia. One of the fundamental challenges of tolerance-inducing protocols is to identify those patients in which the protocol was successful and which can, thus, safely be weaned off immunosuppression. Stable multi-lineage chimerism has long been regarded as the most robust predictor for tolerance and donor T cell engraftment in particular as a critical parameter. The feasibility and safety of this approach have been well established. There has been no transplant-related mortality, few developed acute graft versus host disease (GVHD). Combined bone marrow and kidney transplantation was feasible and that mixed or full donor chimerism, either transient or sustained, could result in long-term renal allograft acceptance without, in some cases, systemic immunosuppression. The broader application of tolerance induction strategies, however, is for patients with organ failure and without an underlying malignancy to avoid the deleterious effects of lifelong immunosuppressive therapy still under evaluation taking into account that GVHD is not an acceptable complication in this patient population and could end with death. Advances in Hematology Volume 2016, Article ID 6471901, 8 pages http://dx.doi.org/10.1155/2016/6471901
There are limited data about bone marrow and kidney transplantation fo MM patients but as mentioned in this article
findings on 10 patients who received combined bone marrow and kidney transplants from HLA single haplotype mismatched living donors. Transient chimerism developed in all recipients and tolerance to donor alloantigens was achieved in majority of patients.
6 patients could not be withdrawn from immunosuppression indefinitely and role of T regulatory cells in development of tolerance was demonstrated.
The time between ASCT and renal transplantation and medications used affected the out come
Optimal treatment of MM consisting of anti-myeloma induction therapy followed by autologous stem cell transplantation (ASCT) and
maintenance therapy is estimated to result in prolonged disease-free remission in 20%. The achievement of complete remission is associated with a 30% chance of non-progression in the following 20 years (1).
only 18 MM patients treated with SCT followed by kidney transplantation have been reported in the literature by Shah et al. Who mentioned that “of our knowledge. Some patients achieved long-term survival without MM relapse and good allograft survival; however, MM relapse, cardiovascular and infectious complications, allograft failure due to rejection and patient death appear to be common in this patient population”.Shah et al.(2)
Also some of induction medications used for MM reported to cause acute kidney injury and graft nephrectomy.
1 Martinez-Lopez J, Blade J, Mateos M-V et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 2011; 118: 529–534.
2 Shah S, Ibrahim M, Delaney M et al. Risk of relapse of multiple myeloma following kidney transplantation: a case series report. Clin Kidney J 2018.
Preclinical models of combined kidney and bone marrow transplantation have shown that the tolerance can be achieved through either transient or sustained hematopoietic chimerism.combined transplant in patients with multiple myeloma have shown that organ tolerance and prolonged disease remission can be accomplished with such approach.
Reference:
Chen Y.B., Kawai T.,Spitzer Th.R. Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance. Advances in Hematology. Volume 2016, Article ID 6471901.
This generally good idea, but big challenge is that we not be able to get well matched HLA in kidney transplantation. The success requires high degree of match and that was the case in bone marrow transplantation. The protocol may not be welcomed worldwide due the toxicities associated with conditioning regimens.
Doaa Elwasly
3 years ago
Tolerance is the ability of a transplanted organ to stay viable without elicting immune response in an immunocmpetent recipient without the need to use immunosuppresives.
Self tolerance is defined as the ability of B and T lymphocytes to maturate differentiating between self and foreign antigens therefore not attacking self antigens.
Central tolerance is a state where Band T lymphocytes reactive against self antigens are clonaly deleted, this is pursued through anergy, deletion then receptor editing .
Peripheral tolerance is done by destroying self T and B lymphocytes through deletion and apoptosis ,anergy then regulation or suppression.
Thymus derived T regulatory controls central tolerance and periphery derived T reg conrtols peripheral tolerance.
Cells are divided into Classical CD4+Foxp3+ Treg cells and CD4+Foxp3− type 1 regulatory T (Tr1) cells, the later is a target to prevent graft rejection.
Signatures of tolerance revealed expression of B cell–related genes and relative expansions of B cell subsets .
Brouard et al., identified a score based on six genes and two demographic parameters and is not affected by immunosuppression, center of origin, donor type or post-transplant lymphoproliferative disorder history.
Lechler et al ,2010 found that tolerant patients are characterised by increased number of peripheral blood B and NK lymphocytes ,lower number of activated CD4+ T cells , absence of donor specific antibodies and donor specific hyporesponsiveness of CD4+ T cells ,high ratio of FoxP3 to α-1,2 mannosidase gene expression , differential expression of B cell related genes and associated molecular pathways
Chimerism is acquired tolerance ;where host and recipient antigens are existing together without being provocative to recipient immune system.
Monozygotic twin expressed acceptable degree of tolerance while dizygotic expressed insufficient tolerance degree.
Microchimerism was noticed in20% of liver transplantation Tolerance can be achieved by
-Cellular therapiesare being developed as mixed chimerism , regulatory T cells, Bcells , macrophage , dendritic cells,myeloid derved suppressor cell and mesenchymal stromal cells
-Tcell depletion as ATG , Alemtuzumab ,
-costimulation blockage as Abatacept,
-T cell therpies as Basiliximab,
-B cell therapies as Ritoximb and Balimumab.
-Irradiation to lymph node , spleen and thymus of limited use,
-Splenectomy
Multiple protocols inducing tolerance in kidney transplant recipients was studied to be able to withdraw immunosuppression as those causing full donor chimerism , transient mixed chimerism and sustained mixed chimerism
Amit Sharma
3 years ago
Concept of tolerance is achieving ultimate goal of a donor organ staying in perfect harmony with recipient body without immunosuppression and with an intact immune system, Tolerance can be immunological tolerance (with no immunological effect on the graft in absence of immunosuppression) or clinical operational tolerance (no histological signs of rejection in absence of immunosuppression for more than 1 year).
Self-tolerance is the concept of ability to prevent proliferation of harmful T or B cells. It can be central or peripheral.
Central tolerance involves destruction of auto-reactive T and B cells by clonal deletion at the central level (Thymus for T cells and Bone marrow for B cells)an immature T cell enters thymus and receives T cell receptor (TCR) and undergoes upregulation of CD4 and CD8 antigen becoming a double positive T cell which reacts with self-peptide. If it shows too strong reaction, it undergoes apoptosis.In presence of a favorable response, T cell matures with either CD4 or CD8 receptor. Central tolerance involves either anergy (poor B cell receptor signalling leading to poorly responding B cells), deletion of self-reacting B cells, or receptor editing (with altered specificity).
Peripheral tolerance involves killing of self-reactive T and B cells (which escape the central tolerance and reach peripheral circulation) by either deletion or apoptosis, anergy (poor response to further antigenic stimulus) or regulation through rregulatory T cells (Treg).
Biomarkers for tolerance (tolerance signatures) have been proposed by various groups and include factors like differential expression of B cell related genes, increased peripheral blood B and NK (Natural Killer) lymphocytes, decreased activated CD4+ T cells, decreased responsiveness of CD4+ T cells, absent DSA, high ratio of FoxP3 to alfa 1,2 mannosidase gene expression etc.
Chimerism is the state of harmonious co-existence of donor and recipient hematopoietic stem cells without any immunological response. Microchimerism is the state of small number of donor cells (less than 1% of all circulating recipeint cells) in the recipient body.
In transplant, tolerance can be achieved at central and peripheral level. Central transplant tolerance can be achieved by destroying the T cell population by methods like total lymphoid irrradiation and donor bone marrow transplant achieving a state of chimerism. Peripheral transplant tolerance can be achieved by using different molecules like ATG (T cell depletion), Abatacept, Belatacept (costimulation blockade), etc. Splenectomy has been used as a method of achieving tolerance by destroying B lymphocytes and IgM antibodies (used in setting of ABO incompatible transplants).
Although progress has been made by following different protocols to achieve tolerance, but their results are still unpredictable and need further refinement.
MICHAEL Farag
3 years ago
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
Self-tolerance
In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens
Central tolerance
a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion
Peripheral tolerance Peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis,
energy, and regulation or suppression
Tolerant patients showed the following characteristics • expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of donor specific antibodies
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Microchimerism is persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. Presence of such microchimerism can occur from pregnancy, blood transfusion and previous transplants. Microchimerism leading to spontaneous operational tolerance
Tolerogenic strategies
Potential impact of cellular therapies, different cellular therapies are still evolving
At present, proposed protocols for inducing tolerance have significant drawbacks in terms of drug toxicity and unpredictable results. Ongoing trials in cellular therapies by the Transplant Research Immunology Group appear to be promising.
Mohamad Habli
3 years ago
In general tolerance means the absence o fimmune system activation in response to specific antigen. In kidney transplantation, tolerance means the absence of immune response to transplanted graft in the absence of immunosuppression while immune system is intact.
During developmental process of B and T cells in the lymphoid system, education and maturation of these cells occur to finally, be released into the systemic circulation with proper function, preventing by this mean, over-reactive immune cells.
this is achieved by central and peripheral tolerance..
Central tolerance is the process in which only T lymphocytes with favorable function are selected to be released into the circulation, however T lymphocytes with strong reaction to self peptides are eliminated. that why only 3-5 % of lymphocytes entering the thymus are selected for further maturation.
Peripheral tolerance is the second step in eliminating self over-reactive T and B cells that escape from the central tolerance mechanism.
Central and peripheral T regulatory cells are the main cells implicating in the regulation of tolerance.
over the past few decades, a lot of studies have been performed to induce tolerance using different strategies,
Cellular therapies which included the use of various immunosuppressive drugs targeting B and T lymphocytes in favor of depletion, inhibition of co-stimulation pathways, or upregulation and proliferation of regulatory T cells.
Other than immunosuppressive drugs, tolerance inducing strategies included total lymphoid tissue irradiation and splenectomy.
clinical application for lymphoid tissue was limited because of adverse events, while splenectomy was used in some countries but controversies exist for its application because of is believed that spleen has role in the induction and maintenance of T regulatory cells.
Many recent protocols that aim to induce tolerance in kidney transplantation to avoid the deleterious side effects of immunosuppressive therapies include protocols achieving full donor chimerism or transient mixed chimerism. protocols use donor stem cell and recipient immune system co-exist with one another to achieve the tolerance.
Wessam Moustafa
3 years ago
Achieving tolerance to transplanted organ has been an important subject of research
Tolerance is defined as ability of foreign tissue or organ to survive in a host , without immunosuppressive drugs , for at least 1 year in immunocompetent individual capable of responding to other stimuli as infections
The idea of transplant tolerance came from the self tolerance phenomenon, in which autoreactive ,harmful B and T cells ( during the process of maturation ) are been discarded ,in order to avoid any harmful immunresponses
Self tolerance is divided in central tolerance ( in thymus gland and bone marrow ) and peripheral tolerance ( in peripheral blood )
Tolerance to transplant was 1st introduced through experimental animal models in 1950 , and was found to happen spontaneously in some of non adherent patients .
Since then studies have been directed to detection of biomarkers for identification patients who may acquire tolerance .
Biomarkers identifying studies have been evolving over years , finally in 2010, lechler and his colleagues performed multicenter study and concluded that tolerant people have the following
Expanded B cells and NK cells
Fewer activated CD4 cells
Expansion of B cell related genes
No DSAs
Donor specific CD4 hyporesponsivness
Increased expression of Foxp3 gene .
Another point, is the discovery of a process called chimerisim in which small amount of donor cells found in recepient blood capable of inducing tolerance ,
This lead the researchers conclude that , interchange of red cell and leukocyte precursors from donor to recipients ,could lead to tolerance between grafts ( a phenomenon discovered from twin cattles that share red cell precursors of its own and its twin at same time without induced immune reponse ) .
Differed tolerogenic strategies have been proposed including :
Cellular theory
Total lymphoid ablation
Splenectomy
Different protocols applying cellular therapies are now promising , including those causing full donor chimerism , transient / permanent mixed chimerism .
Riham Marzouk
3 years ago
Immune Tolerance is the optimum goal we have to reach in order to obtain better graft and patient survival in absence of immunosuppression medications, hence decreased patient morbidity and mortality related to heavy burden of immunosuppressive drugs (ISD).
Definition of tolerance is the ability of the foreign organ to survive in the host without ISD.
Clinical operational tolerance defined as excellent graft function in absence of histological signs of rejection for 1 year in the host and has the ability to respond to surrounding conditions like infections.
Immunological tolerance is the state of acceptance of the graft inside the host or body who exerts no immunological reaction or response to it in absence of ISDs.
Self-tolerance is the ability of Tcells and B cells to learn how to differentiate between self and non self antigens. It is central and peripheral
Central tolerance defined as a process in which auto reactive T and B cells are eliminated; this happened by deletion ( if immature cells are strong self reactive will be deleted).
T cell in thymus are immature if lack T cell receptor TCR and lack CD4 and CD8 antigens called double negative T cell. But if incorporated with the receptor TCR and when upregulation of CD4 and CD8….these cells become mature…usually immature cells die in thymus before reaching periphery, also immature B cells should not react with its receptors and not inducing immune reaction.
Peripheral tolerance any T and B cell escaped from central tolerance will be destroyed in the periphery.
T reg cells are the main cells responsible for immune tolerance , there is thymus derived T reg regulate central tolerance and peripheral derived T reg controls peripheral tolerance, and also there is in vitro induced Treg.
Tolerance signatures are biomarkers indicate tolerance like hyporesponsiveness donor cells , increase Treg cells and decrease activated T cells, no donor specific antibodies.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells. As transplantation between monozygotic identical twin.
Microchimerism presence of donor cells in percent less than 1% from all recipient cells circulating in the patient blood as transplantation between dizygotic twins.
Strategies help tolerance induction:
1- Total irradiation of all lymphoid tissues and organs, this is dangerous and inapplicable.
2- Splenectomy…its limitation is present because its role in induction and maintenance of Treg cells.
There are several tolerogenic protocols include T cell depletion, B cell depletion and co stimulation block.
In addition, there are some strategies still under research and development like T and B reg infusion, mixed chimerism…etc.
transforming growth factor beta TGF-β has an important role to keep suppressive effects of Treg cells which are the key of immune tolerance , it suppress differentiation of original cells also natural killer cells are mediated by TGF-β and has their role against graft versus host disease , so its presence has a role in immune tolerance
M. Sykes. Immune tolerance: mechanisms and application in clinical transplantation. Journal of Internal Medicine. September 2007.Volume 262, Issue3, Pages 288-310.
Over the past few decades, a lot of studies have been performed to induce tolerance using different strategies.
-Cellular therapies which included the use of various immunosuppressive drugs targeting B and T lymphocytes in favor of depletion, inhibition of co-stimulation pathways, or upregulation and proliferation of regulatory T cells. Examples: ATG, Alemtezumab, Betalacept, Efalezumab,Basiliximab, Rituximab, Bortezumab, Eculizumab etc.
-Other than immunosuppressive drugs, tolerance inducing strategies included total lymphoid tissue irradiation and splenectomy. In clinical practice, lymphatic system irradiation is reserved to patients with hematologic malignancies and concomitent end stage renal diseases , in particular multiple myeloma, where total lymphoid irradiation is followed by bone marrow and kidney transplantation.
Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up
Xuanchuan Wang
Methods
From 2009 to 2017
11 donor/recipient pairs underwent living-related kidney transplantation combined with DHSC infusion.
Two of the pairs were human leukocyte antigen (HLA)-matched
nine were HLA-mismatched.
DHSCs were mobilized using granulocyte colony-stimulating factor (G-CSF) and harvested 1 day before transplantation.
The recipients received consecutive total lymphoid irradiation (TLI) for 3 days before kidney transplantation.
The induction drug was anti-thymocyte globulin (ATG).
DHSCs were infused on days 2, 4, and 6 post surgery.
All patients were followed-up until Dec 2019.
Results
Five patients were able to reduce the dose of their immunosuppressive therapy.
mild rejection with Banff grade IA in one patient, while the other ten recipients did not develop rejection.
No increased risk of infections.
One recipient lost allograft function, and 10 recipients had stable renal function.
None developed myelosuppression or GVHD post transplantation.
What are your thoughts about bone marrow and kidney transplantation for patients with multiple myeloma? Do you think this is a tolerogenic strategy? Have you ever heard about such trials?
Specific tolerance has been acheived after combined kidney and bone marrow transplant in multiple myeloma patient as evidenced by prolonged normal renal function without ongoing immunosuppression.
trial
Long-Term Follow-Up of Recipients of Combined Human Leukocyte Antigen-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With End-Stage Renal Disease
Thomas R. Spitzer et al
conclusion- sustained renal allograft tolerance and prolonged antimyeloma responses are achievable after combined kidney and bone marrow Hla matched transplant .
Tolerance in renal transplantation means no immunosuppression is needed in a recipient to avoid rejection of allograft for a sustained period of time.
Donor hematopoietic stem cell transplantation has been used successfully to induce tolerance in clinical kidney transplantation from living donors.
SUMMARY
Tolerance can be-
Clinical operational tolerance-graft like histological signs of rejection without immunosuppression.
Immunological tolerance- no immune reaction against the graft without immunosuppression.
Self tolerance comprises of –
A) Central tolerance-
B cells mature in bone marrow,Tcells mature in Thymus.
when T cells reach thymus they are double negative. their they receive TCR and upregulation of CD4 and CD8 takes place(double positive).in thymic stroma via negative selection self reacting T cells are killed and Via clonal selection non reacting T cells to self are selected and they mature.
Similarly, B cells are also tested for reactivity to self-antigens before they enter the periphery.
B) Peripheral tolerance
By deletion,apoptosis,anergy,regulation or suppression self reaction T and B cells which somehow managed to escape central tolerance are killed.
Main mediator cells of tolerance
Thymus-derived regulatory T (tTreg) cells for central tolerance.
peripherally derived regulatory T (pTreg) cells for peripheral tolerance.
Types of Tolerance signatures or biomarkers
New gene expression signature
Composite score based on 6 genes and 2 demographic parameters.
Characteristics of tolerant patients
expansion of peripheral blood B and NK lymphocytes
fewer activated CD4+ T cells
lack of donor specific antibodies
donor specific hyporesponsiveness of CD4+ T cells
high ratio of FoxP3 to α-1,2 mannosidase gene
expression
differential expression of B cell related genes and
associated molecular pathway.
Chimerism
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.Microchimerism can occur from pregnancy ,blood transfusion and previous transplants.
Tolerogenic strategies
T cell
T cell depletion by using ATG or Alemtuzumab
Costimulation blockade by using Abatacept,Belatacept or Efalizumab.
Others- Basiliximab and Alesleukin plus rapamycin
B cell
Rituximab,Belimumab,Ataicicept,Bortezomib,Eculizumab can be used
Mixed chimerism
Using infusion of donor bonr marrow into myeloablated/immune-conditioned receipient .
Infusion of expanded regulatory T cells.
Tolerance:
In spite having foreign well functioning organ inside a host without the use of immunosuppression , no immune reaction .
Self-tolerance:
It is meaning that during maturation ,T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens preventing them to attack self tissue .
It includes central and peripheral tolerance:
*Central tolerance :
Clonal deletion of the potentially auto-reactive T and B cells .
double negative cell:immature cell which lack both the TCR and the antigen CD4 and CD8
double positive cell: incorporation of TCR with upregulation of the CD4 and CD8 .
negative selection : T-cell are eliminated by apoptosis If they strongly react with react with the peptides in thymic stroma (self-peripheral proteins).
Positive selection: T-cells that interact positively to self-protein and become mature T cells
single positive T cells : mature T cells express either CD4 or CD8 receptors represent 3-5% of the original T cells.
T-cell with very low reaction fail to induce survival signals and die within the thymus.
this process is called clonal selection.
Also the B-cells are tested also for reactivity to self-antigen before they are released to the periphery.
The central immune tolerance is the function of thymus-derived regulatory T-cell (t T reg ).
*Peripheral Tolerance :
is killing the self-reactive T and B cells that escape the central tolerance mechanism and enter the peripheral circulation by either the deletion and apoptosis, energy, and regulation or suppression mediated by Peripheral regulatory T cells (pTreg).
Another classification to Treg cell depend on what they express:
A- Classical CD4+ Foxp3+ Treg cells
B- CD4+Foxp3-type 1 regulatory t cell (Tr1)
These expressers become area of researches with promising hope to prevent transplant rejection.
Tolerance signatures: (biomarkers)
Researchers show more interest in identification of the biomarkers of tolerance, as by validation of these biomarkers, there will chance to predict those recipients that will get tolerance with no immunosuppression or minimal dose.
Tolerant patients showed the following characteristics
• expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of DSA
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism:
It is presence of the donor and host haematopoietic stem cells within the host without causing an immunological reaction against donor cells.
Microchimerism is the presence of donor cells (<1% of all circulating recipient cells) in the recipient body can occur from pregnancy, blood transfusion, and previous transplants.
In liver transplants up to 20% of the recipients develop spontaneous operational tolerance. This can be due to large number of donor leukocytes that come with the transplanted liver and lead to microchimerism in the recipient.
Transplantation between identical monozygotic twins associated with marked tolerance. While, between dizygotic (HLA non-identical) twins, the microchimerism is incomplete and this cause incomplete tolerance.
Tolerogenic strategies
Many protocols have been developed, with an aim to inducing tolerance in kidney transplant recipients. Thereby the immunosuppression can be discontinued.
Cellular therapy to achieve such tolerance are many:
·Total lymphoid elimination protocol includes irradiation of the LN, spleen, and thymus. It has high toxicity. Used in patient with multiple myeloma and co-existing ESRD.
·Splenectomy: splenic irradiation or splenectomy results in elimination of B lymphocytes and Ig M antibodies result in tolerance with immunosuppression. This regime result in graft survival rate exceeding 90% at 5 years.
·Multiple receptor ligand interactions blockade induces transplant tolerance by activation of T cell energy.
·Costimulatory pathways CD 28 receptor that bind to CD80 and CD86 ligands expressed on Ag-presenting cell.
Dear All
You read this article.
What is meant by tolerance in your own words?
Have we managed to achieve tolerance?
Tolerance ; is a state of permanent immunological acceptance of allograft by the host immune system in the absence of immunosuppression.
Self tolerance : as T cells and B cells undergo education and maturation in the central lymphoid tissues ,during this process T and B cells learn to differentiate between self and non self antigen .it is a kind of surveillance mechanism to prevent expansion of potentially harmful auto reactive T and B cells .
1.central tolerance in which potentially auto reactive T and B cells are removed by anergy , deletion and receptor editing
2.peripheral tolerance : sweeper mechanism of destroying these self reactive T and B cells that escaped central tolerance through deletion ,apoptosis , energy and regulation or suppression
the main mediators for tolerance are
a.thymus derived regulatory T cells responsible for central tolerance
b. peripherally derived regulatory T cells responsible for peripheral tolerance
c.induced regulatory T cells in vitro
Tolerance signatures or biomarkers
tolerant patients showed the following criteria :
1.expansion of peripheral blood B and NK cells
2.fewer activated CD4+ T cells
3.lack of DSAs
4.donor specifc responsiveness of CD4+ T cells
5.higher rate of FoxP3 to alpha 1 and 2 mannosidase gene expression
Chimerism
is co-existence of donor and host haematopiotic stem cells inside the host without inducing an immunological reaction against donor cells. as occur in transplantation between genetically identical monozygotic twins
Micro chimerism : is persistence of a small number of donor cells less than 1% of all circulatory cells within recipient body leading to spontaneous operational tolerance.
this may occur in liver transplant due to leukocytes coming within the transplanted organ
Tolerogenic strategies
T cell depletion , co stimulation blockade
or current cellular therapy in development as mixed chimerism , regulatory T cells or B cells
2.total lymphoid tissue elimination protocols by irradiation of lymph nodes , spleen and thymus ,but clinical application is limited due to toxicity
3.splenectomy especially in ABO incompatible patients
Successful protocols to achieve tolerance
achieving full donor chimerism
achieving transient mixed chimerism
achieving sustained mixed chimerism
Summary:
—————-
The word tolerance come from the original latin term tolera its indicate the condition when a-forieng tissue or organ engrafted in a-host with clinical and immunological accepatncein the abscence of immunsuppressions.
still alot of researches are ongoing in this field of transplant immunology and its the dream and hope to most of us to reach the state oragn tolerance with out the side effect and cost of the currnet immunsuppressions
Self tolerance :
both T and B cells controls the immune system protecting the host from foreign pathogens which have important role in self-tolerance and non -self( foreign ) tolerance
induction of tolerance involve many mechanisims at the cellular levels both T and B Cells after migartion to the peripheral lymphiod tissues in the precence of TCR and antigenic activation to CD4-CD8 T-cells, which called double postive thymocytes and according to the avidity ofself response will undergo either negative clonal depletion by apoptosis or postivesingle clonal selction .
Central tolerance:
is the most important process by which
the potentially auto-reactive T and B cells are eliminated by a
process called clonal deletion .
Thymus-derived regulatory T (tTreg) cells are considered main mediators of central immune tolerance, whereas peripherally derived regulatory T (pTreg) cells function to regulate peripheral immune tolerance. A third type of Treg cells, termed iTreg, represents only the in vitro-induced Treg cells.
peripheral tolerance:
Peripheral tolerance is the sweeper mechanism of destroying those self-reactive T and
B cells that somehow escaped central tolerance mechanism and end up in the peripheral
circulation.
Tolerance signature:
pontaneous operational tolerance has been achieved in non-adherent transplant patient, buarad etal reported 27 cases of traplsnat tolerance
Immunosuppression may affect ‘Tolerance signatures’ and biomarkersof tolerance includes the following
-Differential expression of B-cell related genes.
– Expansion of peripheral B-cells and NK cells.
– Few activated CD4+ve cells.
– Lack of DSA.
– High ratio of Foxp3 / alpha1,2 mannosidase gene expression.
– Chimirsim
means an acquired Tolerance. co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerance startagies :
-Trials of Cellular therapies in development
–Tolerance is achieved by irradiating the lymph nodes, spleen and thymus.
-Splenectomy
Biomarkers of tolerance have been described and include the following :
– Differential expression of B-cell related genes.
– Expansion of peripheral B-cells and NK cells.
– Few activated CD4+ve cells.
– Lack of DSA.
– High ratio of Foxp3 / alpha1,2 mannosidase gene expression.
Chimerism has been described as co-existence of donor and host stem cells inside the host without induction of immune response. Different protocols have been tried for induction of chimerism like :
– Full donor chimerism.
– Transient mixed chimerism.
– Sustained mixed chimerism.
Tolerogenic strategies have been developed to induce tolerance and include the following :
– Cellular therapies as total lymphoid elimination by irradiation of the thymus,
spleen and lymph nodes. however, this therapy is highly toxic.
– Splenectomy as spleen is important in B-cell maturation and IgM production.
1- differential expression of B-cell related genes.
2- expansion of peripheral B-cells and NK cells.
3- few activated CD4+ve cells.
4- lack of DSA.
5- high ratio of Foxp3 / alpha1,2 mannosidase gene expression.
1- full donor chemerism.
2- transient mixed chemerism.
3- sustained mixed chemerism.
1- cellular therapies as total lymphoid elimination by irradiation of the thymus,
spleen and lymph nodes. however, this therapy is highly toxic.
2- splenectomy as the spleen is critical in B-cell maturation and production of
IgM. it was used in Japan for ABO incompatible grafts. however, the spleen
is also important for development of Tregs.
First of all tolreance is our dream in kidney tansplantation
Tolerance means that the ability of foreign tissue or organ to survive in host without immunosuppressant
Means permanent acceptance of allograft by host immune system in the absence of immunosuppressant
-self tolerance
T&B cells learn to differentiate between self and foreign AG
-central tolerance
T&B lymphocytes mature in thymus &bonemarrow When it reach thymus immature cell undergo rearrangement process to become double positive thymocyte that react with self peripheral protein to eliminate cells with strong reaction to elicit benine Cells for maturation to become single positive Tcell
-peripheral tolerance
Sweeper of T&B cells that escape central tolerance
-tolerance signature
Patient on immunosuppressant have different signature ( biomarker)from patient not recieved
-chimerism
Co existence of donor &recipient heamtopoitic stem cell inside recipient without immunological response.
Noted in cattle twins shared common placenta red cell chimerism extended to adulthood , indicate that exposure to non self AG in utero on neonatal can led to micro chimerism.
Tolerance strategies:
– total lymphoid elimination (limited use in M.M
-spleenectomy;done in japan in ABO incompatibility
-T-cell depletion by ATC or alemtozumab
-costimulation blockade by belatacept or efalizumab
-other T-cell therapies as basileximab ( interlukin 2 antagonist)
-Rituximab ,belimumab,atacicept ( B-cells)
-bortizomab apoptosis of plasma cells
-Eculizumab anti interlukin 6
Mixed chimerism
-infusion of donor bone marrow into recipient for producing co-exsitance of donor and recipient cells.
-regulatory T-cell,dendritic cells,regulatory B-cell,macrophages,myloid derived suppresor cell
Full chimerism:
-MGH protocol: HLA matched related donor kidney &bone marrow transplant for heamatogic malignancy .
-MGH protocol: haploidentical donor kidney &bone marrow transplant in heamatogic malignancy .
-North western protocol:haploidentical /mismatch related& unrelated kidney & bone marrow transplant for ESRD without malignancy.
Tolerance is the ability of an organ to survive in a foreign individual without any immunosuppression. It is basically a donor specific non reactivity by the recipient. Clinical tolerance is defined as a well accepted graft lacking signs of histological rejection for atleast 1 year after transplant. The concept of tolerance is best understood through learning about self tolerance. In the developmental process of the lymphoid tissue both T cells and B cells undergo education and maturation in the central lymphoid organs (bone marrow and thymus). During this process T and B cells learn to differentiate between self and non self.
Deletion and apoptosis – Apoptosis induced cell death is mediated by binding of
Fas (CD95) with its ligand FasL (CD 95L) on T Cells
Anergy – Hyporesponsiveness of T or B cells to further antigenic stimulation in the
absence of costimualtion
Regulation and Suppression – it is done by T regulatory cells’ also called Treg
cells. which are either thymus derived or in the periphery
Tolerance is the holy grail in renal transplantation. Tolerant patients usually show expansion of peripheral blood B and NK lymphocytes, fewer activated CD 4 T cells, lack of DSA, donor specific hyporesponsiveness of CD 4 Tcells, high ratio of FOXP 3 gene expression. This study was published in 2010 and it showed the above as a measure of operational tolerance
The current strategies used for tolerance are
Chimerism: is state of coexistence of donor and host hematopoeitic stem cells inside the host without inducing an immunological reaction against donor cells. The phenomenon of microchimerism is when <1% of the donor cells are within the recipient body during blood transfusion, pregnancy and previous transplants. It is seen in 20% of liver transplants where a large number donor leucocytes come into the transplanted liver due to portal circulation
Chimerism can be full donor chimerism where 100% of bone marrow and blood cells are of donor origin. Mixed chimerism is when both donor and recipient hematopoeitic stem cells reside in the recipient without inducing an immunolgical reaction. Mixed chimerism can be sustained or transient. 3 universities namely MGH, Standford and North western University have published their vast experience in the field of chimerism and rena transplant to achieve tolerance. Total body lymphoid irradiation was used in MGH protocol in cases of multiple myeloma and coexisting ESRD. Many of these patients were off immunosuppressives after an average of 6 months after transplants. tolerance was achieved in a variable number from 40-60% across the 3 studies
Tolerance:
Inability of a foreign tissue or organ to survive in a host without immunosuppression.
Clinical operational tolerance:
Is described as a well-functioning graft lacking histological signs of rejection in absence
of immunosuppression for at least 1 year in an immunocompetent.
Immunological tolerance:
No detectable immune reaction towards the allograft in absence of
immunosuppression. It is a state of permanent and specific c immunological acceptance
of the allograft.
Self-Tolerance:
T and B cells learn to differentiate between self-antigens and non-self (foreign antigen).
Central tolerance:
is the most important process by which the potentially auto-reactive T and B cells are
eliminated by a process called clonal deletion.
Peripheral tolerance:
Peripheral tolerance is the sweeper mechanism of destroying those self-reactive T and
B cells that somehow escaped central tolerance mechanism and end up in the
peripheral circulation.
Tolerance signatures:
Tolerant patients showed the following characteristics • expansion of peripheral blood B
and NK lymphocytes • fewer activated CD4+ T cells • lack of donor specific c antibodies,
Donor specific hypo responsiveness of CD4+ T cells • high ratio of FoxP3 to α-1, 2
mannosidase gene expression • differential expression of B cell related genes and
associated molecular pathways
Chimerism:
is co-existence of donor and host hematopoietic stem cells inside the host without
inducing an immunological reaction against donor cells.
Microchimeric:
Is persistence of a small number of donor cells (less than1% of circulating recipient cell)
in the recipient body.
Presence of such Microchimeric can occur from pregnancy, blood transfusion and
previous transplants
. Microchimeric leading to spontaneous operational tolerance has been seen in up to
20% of liver transplants.
Tolerance strategies:
Successful protocols with the aim of inducing tolerance in kidney transplant recipients
enabling immunosuppression to be discontinued.
Total lymphoid elimination protocols:
Tolerance is achieved by irradiating the lymph nodes, spleen and thymus.
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-hematopoietic chimerism.
Splenectomy:
Splenic irradiation or splenectomy resulting in a state of tolerance. This strategy was
commonly used in Japan for ABO incompatible transplants.
Cellular therapies:
T cell depletion
ATG: T-cell depletion in blood and peripheral lymphoid tissues through complement-
dependent.
Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
Costimulation blockade
Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
Other T cell therapies:
Basiliximab: Blockade of CD25.
Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and
stabilise the expression of FoxP3
B cell therapies
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
Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand).
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies in development.
Mixed chimerism:
Infusion of donor bone marrow into myoablated /immune-conditioned recipient for
producing co-existence of donor and recipient cells.
Regulatory T cells:
Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production,
down-regulate costimulatory and adhesion molecules, promote anergy and cell death,
convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL-
10,TGF-B and IL35.
Dendritic cells
Deletion of T cells, induction of Trigs and anergy T cells, expression of
immunomodulatory molecules and immunosuppressive factors.
Macrophages
Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and caspase dependent
depletion of activated T cells.
Myeloid derived suppressor cell
Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-
Y producing T cells
Mesenchymal stromal cells:
Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T
cells and downregulation of MHC Class II and co-stimulatory molecules
Regulatory B cells
Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM,
expression of Fas-L.
Successful protocols with the aim of inducing tolerance in kidney transplant
recipients enabling immunosuppression to be discontinued are :
Full donor chimerism protocol:
Massachusetts General Hospital protocol (MGH):
Transient mixed chimerism:
Massachusetts General Hospital protocol
Sustained mixed chimerism : Sanford hospital protocol.
Tolerance:
Inability of a foreign tissue or organ to survive in a host without immunosuppression.
Clinical operational tolerance:
Is described as a well-functioning graft lacking histological signs of rejection in absence
of immunosuppression for at least 1 year in an immunocompetent.
Immunological tolerance:
No detectable immune reaction towards the allograft in absence of
immunosuppression. It is a state of permanent and specific c immunological acceptance
of the allograft.
Self-Tolerance:
T and B cells learn to differentiate between self-antigens and non-self (foreign antigen).
Central tolerance:
is the most important process by which the potentially auto-reactive T and B cells are
eliminated by a process called clonal deletion.
Peripheral tolerance:
Peripheral tolerance is the sweeper mechanism of destroying those self-reactive T and
B cells that somehow escaped central tolerance mechanism and end up in the peripheral
circulation.
Tolerance signatures:
Tolerant patients showed the following characteristics • expansion of peripheral blood B
and NK lymphocytes • fewer activated CD4+ T cells • lack of donor specific c antibodies,
Donor specific hypo responsiveness of CD4+ T cells • high ratio of FoxP3 to α-1, 2
mannosidase gene expression • differential expression of B cell related genes and
associated molecular pathways
Chimerism:
Chimerism is co-existence of donor and host hematopoietic stem cells inside the host
without inducing an immunological reaction against donor cells.
Microchimerism:
Is persistence of a small number of donor cells (less than1% of circulating recipient cell)
in the recipient body.
Presence of such Microchimerism can occur from pregnancy, blood transfusion and
previous transplants.
. Microchimerism leading to spontaneous operational tolerance has been seen in up to
20% of liver transplants.
Tolerance strategies:
Successful protocols with the aim of inducing tolerance in kidney transplant recipients
enabling immunosuppression to be discontinued.
Total lymphoid elimination protocols:
Tolerance is achieved by irradiating the lymph nodes, spleen and thymus.
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-hematopoietic chimerism.
Splenectomy:
Splenic irradiation or splenectomy resulting in a state of tolerance. This strategy was
commonly used in Japan for ABO incompatible transplants.
Cellular therapies:
T cell depletion
ATG: T-cell depletion in blood and peripheral lymphoid tissues through complement-
dependent.
Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
Costimulation blockade
Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
Other T cell therapies
Basiliximab: Blockade of CD25.
Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and
stabilise the expression of FoxP3.
B cell therapies
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.
Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand)
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells.
Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies in development.
Mixed chimerism:
Infusion of donor bone marrow into myoablated /immune-conditioned recipient for
producing co-existence of donor and recipient cells
Regulatory T cells
Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production,
down-regulate costimulatory and adhesion molecules, promote anergy and cell death,
convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL-
10,TGF-B and IL35
Dendritic cells
Deletion of T cells, induction of Trigs and anergy T cells, expression of
immunomodulatory molecules and immunosuppressive factors
Macrophages
Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and caspase dependent
depletion of activated T cells
Myeloid derived suppressor cell
Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-
Y producing T cells.
Mesenchymal stromal cells
Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T
cells and downregulation of MHC Class II and co-stimulatory molecules.
Regulatory B cells
Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM,
expression of Fas-L.
Successful protocols with the aim of inducing tolerance in kidney transplant
recipients enabling immunosuppression to be discontinued are :
Full donor chimerism protocol:
Massachusetts General Hospital protocol (MGH):
Transient mixed chimerism:
Massachusetts General Hospital protocol.
Sustained mixed chimerism : Sanford hospital protocol.
our main aim in kidney transplantation is to induce tolarance , wich means to make the host body to accept the graft as a self ( ORGAN ) antigen .
self tolerance : means that the lymphoid tissue ( T,B cells ) lern to recognize the patients antigens as aself one whithout inducing reaction against them .
central deletion : is the process of elimination of auto reactive B and T cells by clonal delletion .
chimersim : is the presence of both donor and host hematopoitic stem cells inside the host without induction any immunological reaction.
tolarogenic strateges :
Strategy
T cell depletion —
ATG AND ALEMTUZMAB
Costimulation blockade —- BELATOCEPT , ABATACEPT AND EFALIZUMAB
Other T cell —— Basiliximab , Aldesleukin + Rapamycin:
therapies
B cell therapies :
Rituximab , Belimumab , Atacicept , Bortezomib , Eculizumab .
CELLULAR THERAPY IN DEVELOPMMENT :
Mixed chimerism , Regulatory T cells , Dendritic cells , Macrophages , Myeloid derived suppressor cell , Mesenchymal stromal cells , Regulatory B
cells
THERE IS MANY DESIYNED PROTOCOLS AT DIFFRENT CENTERS WITH PROMISING RESULT .
Clinical operational tolerance, prescribed as well functioning graft with the following features;
1- no histological signs of rejection
2- off immunosuppressant for at least one year
3- host is immune competent
Immunological tolerance ; means no immune reaction towards the allograft in the absence of immunosuppressant.
Self tolerance; during early period of development T and B lymphocytes learn how to differentiate between self and none self antigens and it is classified into central and peripheral types.
Central tolerance; in which auto reactive T and B cells are eliminated by process called clonal deletion .
Clonal deletion of T cell; T cells mature in the thymus ,when they reach the thymus are lack (TCR ,CD4 and CD8)and are called double negative. In the thymus are incorporated with TCR and up regulated with CD4 or CD8 and are called double positive.
Double positive T cells start reacting with peptides in thymic stroma (self peripheral protein).
T cells that react too strongly with self peptide are eliminated by apoptosis (negative selection).
T cells that react favorably with self peptide are in turn positively selected and eventually become mature T cell that express either CD4 or CD8 receptor.
Cells with very low avidity interactions fail to induce survival signals and die within thymus.
3 – 5% of original T cells ,that enter the thymus are positively selected and end up as mature T cell.
Clonal deletion of B cell; the same like T cell.
Peripheral tolerance; is the mechanism of destruction of self reactive T and B cells ,that somehow escaped central tolerance mechanism, via one of the following mechanism; deletion ,apoptosis ,energy or (regulation or suppression )B cells .
Tolerance signature ;
Spontaneous tolerance has been achieved in none adherent patient.
Tolerant patients showed the following characteristics;
– Expansion of peripheral blood B and NK lymphocytes
– Fewer activated CD4+ T cells.
-Lack of donor specific antibodies.
– Donor specific hyporesponsiveness of CD4+ T cells
– high ratio of FoxP3 to α-1,2 mannosidase gene
expression.
– Differential expression of B cell related genes and
associated molecular pathways
Chimerism;
Co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells .
Microchimerism;
Persistence of a small number of donor cells within the recipient body ,which can occur from pregnancy ,blood transfusion and previous transplant .
It can lead to spontaneous operational tolerance.
Tolerogenic strategies;
-Cellular therapy
-Total lymphoid elimination protocols
-splenectomy
●Tolerance is the ability of a foreign tissue or organ to survive
in a host without immunosuppression.
●“Immunological tolerance” is no detectable immune
reaction towards the allograft in absence of immunosuppression.
It is a state of permanent and specifi c immunological acceptance
of the allograft by the host immune system in the absence of
immunosuppression
●Self-tolerance: T and B-lymphocytes,
controls the immune system protecting the host from foreign
pathogens. In the developmental pathway of the lymphoid
system, T cells and B cells undergo education and maturation
in the central lymphoid organs; the thymus and bone
marrow. During this maturation process, T and B cells learn
to differentiate between self-antigens and non-self (foreign)
antigens
●Central tolerance
In the affinity-avidity model, self-tolerance comprises of
central and peripheral tolerance and can be described as a kind
of surveillance mechanism to prevent expansion of potentially
harmful auto-reactive T and B cell clones
●Peripheral tolerance
Peripheral tolerance is the mechanism of
Cleaning those self-reactive T and B cells that somehow
escaped central tolerance mechanism and end up in the
peripheral circulation. They are controlled in the periphery
by one of the following mechanisms: deletion and apoptosis,
energy, and regulation or suppression
●‘tolerance signatures’ ara biomarkers has been of
immense interest as validation of these biomarkers across
different set of populations will aid in formulating predictive
models for identifying those recipients that will achieve
tolerance with minimal or no immunosuppression long term.
●Chimerism
Chimerism is co-existence of donor and host haematopoietic
stem cells inside the host without inducing an immunological
reaction against donor cells.
●Tolerogenic Strategies :
1:Cellular therapies ; e.g. T cell depletion( ATG, Alemtuzumab, Basiliximab, Aldesleukin+ Rapamycin, Rituximab, Belimumab). Costimulation blockade( Abatacept, Belatacept, and Efalizumab). B cell therapy( Atacicept, Bortezomib)
2;Total lymphoid elimination protocols ; This protocol uses irradiation, and is more toxic therapy. The only indication is Multiple Myeloma+ ESRDSplenectomy; The idea is get rid of circulating antibodies. This technique is popular in Japan for ABO incompatible transplant. However current literature demonstrated the role of spleen in induction and maintenance of regulator CD4 T cell, and there fore induces self tolerance. Other therapies are in the stages of development.
●Successful Protocols with the aim of inducing tolerance in kidney transplant allowing immunosuppression to be withdrawn ;
Full donor chimerism ;
Transient mixed chimerism protocol ; Sustained mixed chimerism protocols ;
Tolerance:
Definition: tolerance is to have foreign organ survive in a host, without the use of immunosuppression.
Types:
1- Clinical operational tolerance
It is well functioning graft with no histological features of rejection without the use of immunosuppression drugs for at least one year in an immunocompetent host which is able to respond to infections or other triggers to the immune system.
2- Immunological tolerance
It is a state of complete immunological acceptance of the allograft by the host immune system without the use of immunosuppression.
Self-tolerance:
The lymphoid system, T-cells and B-cells during their maturation in the thymus and bone marrow learn to differentiate between self-antigen and non-self-antigens. It is oversight mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. It includes central and peripheral tolerance.
Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
T-cell reach the thymus as immature cell which lack both the TCR and the antigen CD4 and CD8, this cell called double negative cell. In the thymus; incorporation of TCR with upregulation of the CD4 and CD8 to this cell occur, and this cell called double positive cell. Double positive T cells then react with the peptides in thymic stroma (self-peripheral proteins). T-cell than strongly react are eliminated by apoptosis (negative selection) while T-cells that interact positively to self-protein are selected positively and become mature T cells and express either CD4 or CD8 receptors, so become single positive T cells. this process is called clonal selection. T-cell with very low reaction fail to induce survival signals and die within the thymus. The mature T-cells leaving the thymus represent 3-5% of the original T cells. the B-cell as well undergo the test for reactivity to self-antigen before they are released to the periphery. The central immune tolerance is the function of thymus-derived regulatory T-cell (pTreg).
Peripheral Tolerance is a mop mechanism of killing the self-reactive T and B cells that escape the central tolerance mechanism and enter the peripheral circulation. They are removed by either the deletion and apoptosis, energy, and regulation or suppression. The peripheral immune tolerance is done by the Peripheral regulatory T cells (pTreg).
Induced T regulatory cell (iT cell) induced in vitro, is a third type of Treg cells.
Another classification to Treg cell depend on what they express:
A- Classical CD4+ Foxp3+ Treg cells
B- CD4+Foxp3-type 1 regulatory t cell (Tr1)
These expressers become area of researches with promising hope to prevent transplant rejection.
Tolerance signatures: (biomarkers)
Researchers show more interest in identification of the biomarkers of tolerance, as by validation of these biomarkers, there will chance to predict those recipients that will get tolerance with no immunosuppression or minimal dose.
tolerance signatures in kidney transplants include immunosuppression effect and differential expression of B-cell-related genes and relative expressions of B-cell subsets. Gene expression signature reliably identify patients suitable for immunosuppression drug reduction.
Brouard et al, have identified a composite score which discriminates operationally tolerant patients, the score is associated with both de novo anti-HLA antibodies and tolerance loss.
Chimerism
It is living of the donor and host haematopoietic stem cells inside the host without causing an immunological reaction against donor cells.
Microchimerism is the presence of donor cells (<1% of all circulating recipient cells) in the recipient body. This phenomenon can occur from pregnancy, blood transfusion, and previous transplants. In liver transplants up to 20% of the recipients develop spontaneous operational tolerance. This can be due to large number of donor leukocytes that come with the transplanted liver and lead to microchimerism in the recipient.
Transplantation between identical monozygotic twins associated with marked tolerance. While, between dizygotic (HLA non-identical) twins, the microchimerism is incomplete and this cause incomplete tolerance.
Tolerogenic strategies
Many protocols have been developed, with an aim to inducing tolerance in kidney transplant recipients. Thereby the immunosuppression can be discontinued.
Cellular therapy to achieve such tolerance are many:
· Total lymphoid elimination protocol includes irradiation of the LN, spleen, and thymus. It has high toxicity. Used in patient with multiple myeloma and co-existing ESRD.
· Splenectomy: splenic irradiation or splenectomy results in elimination of B lymphocytes and Ig M antibodies result in tolerance with immunosuppression. This regime result in graft survival rate exceeding 90% at 5 years.
· Multiple receptor ligand interactions blockade induces transplant tolerance by activation of T cell energy.
· Costimulatory pathways CD 28 receptor that bind to CD80 and CD86 ligands expressed on Ag-presenting cell.
Ø 1-T-cell depletion ex: 1-ATG
2-Alemtuzumab (monoclonal Abs depletion)
Ø Co-stimulation blockade: 1- Abatacept, belatacept (block CD28: CD80/86)
2-Elalizumab (block LFA-1:ICAM1
Ø Other T-cell therapy: basiliximab: (block CD25)/ Aldesleukin
Ø 2- B-cell therapy: Rituximab (CD20 blocker)// Belimumab (block BAFFB cell activating factor/ Atacicept// Eculizumab
There are new developing strategies in development from these are: regulatory T cell, dendritic cells, and others
Successful protocols with the aim of inducing tolerance in
kidney transplant recipients enabling immunosuppression to
be discontinued are listed as follows:
Protocols achieving full donor chimerism
Protocol achieving transient mixed chimerism
Protocol achieving sustained mixed chimerism
Tolerance is the ability of the transplanted tissue or organ to stay alive with the host in absence of immunosuppression. Therefore it should show no signs of rejection on histology and no signs of immunologic reaction mounted against it. a lots of work have been done to achieve tolerance but still we are lagging behind and we still dreaming about it.
Tolerance originate from Latin ward tolero i.e to endure(1). Tolerance is co-existence of foreign organ in the host without the need foe immunosuppression. Clinical operational tolerance is where graft survives with histological features of rejection in absence of immunosuppression(3),(4). Immunological tolerance means no immune reaction directed to allograft in absence of immunosuppression .During development of lymphocytes in the thymus ,they learn how to differentiate self from non-self antigens. Central tolerance is when autoreactive T and B cells are cleared by clonal deletion in the thymus. Peripheral tolerance is elimination of the autoreactive T and B cells which bypasses central tolerance mechanism and researches systemic circulation. The mechanisms are deletion, apoptosis, energy and regulation or suppression(8 – 10). Regulatory T cell( thymus and peripheral) are important mediators of the immune tolerance( immune modulatory functions).
CONCLUSION ; Tolerance is still our dream in transplantation science. partial tolerance has been reported in renal transplantation in the setting of non-adherance. The suggested protocols for induction of tolerance is hampered by the highly toxic regiments. Despite all these obstacle people are still working very hard to study more and more about the biology of tolerance.
TOLERANCE MEAN THAT THE BODY DEAL WITH THE EXISTING FOREIGN ANTIGEN WITHOUT DISPLAYING ANY SIGNIFICANT IMMUNE REPONSE.
ACCOMODATION MEAN THAT THE BODY DISPLAYS LESS SIGNIFICANT IMMUNE RESPONSE TO EXISTING FOREIGN ANTIGEN ,BUT OVERALL NO SIGNIFICANT INJURY.
SUMMARY OF THE ARTICLE
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression. It can be described as donor specific non-reactivity in experimental models .
Clinical operational tolerance is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
Immunological tolerance is no detectable immune reaction towards the allograft in absence of immunosuppression.
In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens.
Self-tolerance comprises of central and peripheral tolerance and can be described as a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones
Central tolerance
Mechanism of central tolerance:
Peripheral tolerance
Mechanism of peripheral tolerance:
Tolerance signatures (tolerance biomarkers)
Tolerant patients showed the following characteristics according to Lechler et al. In 2010:
Chimerism
Tolerogenic strategies
1.Cellular therapies: Potential impact of cellular therapies (Transplant Research Immunology group) has been extensively investigated by Wood K et al.
2.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.
3.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 transplants.
Different cellular therapies and it’s mechanism of actions :
1.T cell depletion:
2. Costimulation blockade:
3.Other T cell therapies:
4.B cell therapies:
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.
Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand)
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies in development:
1.Mixed chimerism; Infusion of donor bone marrow into myoablated /immune-condition ed recipient for producing co-existence of donor and recipient cells.
2.Regulatory T cells: Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production, down-regulate costimulatory and adhesion molecules, promote anergy and cell death, convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL- 10,TGF-B and IL35
3.Dendritic cells: Deletion of T cells, induction of Tregs and anergic T cells, expression of immunomodulatory molecules and immunosuppressive factors
4.Macrophages: Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and casp ase dependent depletion of activated T cells.
5.Myeloid derived suppressor cell: Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-Y producing T cells.
6.Mesenchymal stromal cells: Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T cells and downregulation of MHC Class II and co- stimulatory molecules
7.Regulatory B cells: Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM, expression of Fas-L .
Successful protocols with the aim of inducing tolerance in kidney transplant recipients enabling immunosuppression to be discontinued are listed as follows:
Protocols achieving full donor chimerism:
Protocol achieving transient mixed chimerism:
Protocol achieving sustained mixed chimerism:
Tolerance is the ability of the immune system of recipient to recognize the donor organ as self antigen without using immunosuppressive .
Clinical operational tolerance functioning graft without histological features of rejection for at least one year without immunosuppression in otherwise immunocompetent person that can react normally to infection.
Immunological tolerance mean there is no serological immune response to graft in absence of immunosuppression.
Self tolerance is the ability of T & B cells recognize between self & non self antigen during their maturation in thymus & bone marrow. it include central & peripheral tolerance.
Central tolerance refer to destruction of reactive T & B cells by clonal deletion while peripheral tolerance refer to destruction of reactive T &B cells that escaped the central tolerance & present in peripheral circulation ( destruction by deletion & apoptosis, energy, regulation or suppression).
Chimerism is the presence of both recipient & donor hematopoietic stem cells inside the host without activation of immune response against donor cells. Micro chimerism is the presence of small number of donor cells in recipient circulation secondary to pregnancy, blood transfusion & previous transplantation.
There are different strategies to induce tolerance as:
Several successful protocols used to induce tolerance in renal transplant including:
Tolerant patients showed the following characteristics
1-expansion of peripheral blood B and NK lymphocytes
2-fewer activated CD4+ T cells.
3-lack of donor specific antibodies.
4- donor specific hyporesponsiveness of CD4+ T cells.
5-high ratio of FoxP3 to α-1,2 mannosidase gene
expression.
6-differential expression of B cell related genes and associated molecular pathways.
Mangement to achieve tolerance.
**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.
** Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance.
Tolerance In Transplantation:
*Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
*Clinical operational tolerance: is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
* Immunological tolerance is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
* Self tolerance includes central and peripheral tolerance .
* Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
* peripheral tolerance controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression .
* Tolerance signature is for identifying those recipients that will achieve tolerance with minimal or no immunosuppression long term.
* Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cell.
* Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance . However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance .
*Tolerogenic strategies:
-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 treatment.
-Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance. But has clinical limitations as that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for
self-tolerance.
Tolerance in Transplantation
Tolerance is the ability of foreign tissue or organ to survive in the host without immunosuppression.
Clinical operational tolerance is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infection.
Immunological tolerance is no detectable immune reaction toward the allograft in absence of immunosuppression.
Self-tolerance
The lymphoid system consists of T and B lymphocytes which are undergoing eduction and maturation in central lymphoid organs (thymus and bone marrow) and during this process T and B, cells learn to differentiate between self-antigens and non-self antigens.
Central tolerance
It is the most important process by which potential autoreactive T and B cells are eliminated by a process called a clonal deletion.
Peripheral tolerance
It sweeper mechanism of destroying that self-reactive T and B cells which somehow escaped the central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy and regulation, or suppression.
Tolerance signature
Immunosuppression may affect tolerance signatures Immunosuppression may affect ‘Tolerance signatures’ and biomarkers may be different in those with established tolerance as compared to those on immunosuppression.
In 2010 Lechler et al study, tolerant patients showed the following characteristics :
1. expansion of peripheral blood B and NK lymphocyte
2. fewer activated CD4 T cells
3. Lack of donor-specific antibodies.
4. donor-specific hyporesponsiveness of CD4 T cell.
5. the high ratio of foxP3to α1,2mannosidase gene expression
6. the differential expression of B cell-related genes and associated molecular pathways.
Chimerism
It is the co-existence of donor and host hematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Transplantation between genetically identical monozygotic twin has shown the remarkable result of tolerance but among dizygotic twin, the microchimerism is incomplete and lead to inadequate tolerance.
Microchimerism is the persistence of a small number of donor cells( 1%of all circulating recipient cells) within the recipient body occur from pregnancy, blood transfusion, and previous transplantation.
Tolerogenic strategies :
Total lymphoid elimination protocol :This is achieved by irradiating the lymph nodes, spleen, and thymus. Clinical application is limited due to the high toxicity of this kind of treatment.
Splenectomy: Splenic irradiation results in the elimination of B lymphocytes and IgM that result in a state of tolerance.
Splenectomy with other immunosuppressive regimens resulted in a graft survival rate exceeding 90% at 5 years according to a Japanese study.
The clinical limitation of splenectomy, studies have shown that the spleen is important for induction and maintenance of regulator CD4 CD25 T cells which are important for self-tolerance.
Strategy T cell depletion:
1. ATG: it depletes T –cell blood and peripheral lymphoid tissues.
2.Alemtuzumab: it depletes monoclonal antibody to CD52 on T, B, NK.
Costimulation blockade:
1.Abatacept, belatacept: Blockade of CD28:CD80/86 co-stimulatory pathway.
2.Efalizumab: ICAM-1 co-stimulatory pathway blockade.
Other T cell therapies:
1.Basiliximab: Blockade of CD25.
2.Aldesleukin+Rapamycin: They increase T cell proliferation and survival, and stabilize the expression of FoxP3.
B cell therapies:
1.Rituximab: it depletes monoclonal antibodies to CD20.
2..Belimumab: it blocks BAFF B activation.
3.Atacicept: it blocks BAFF and APRIL.
4.Bortezomib: It proteasome inhibitor.
5.Eculizumab: it blocks complement protein C5.
*Tolerance is the ability of the foreign organ to survive in the body of recipient without any immunosuppression without increased risk for infections .
*Clinical operational tolerance entails a well-functioning allograft in the absence of histological evidence of rejection without immunosuppression in an immunocompetent recipient for at least 1 year .
*Central tolerance is by which autoreactive T-cells and B-cells by clonal deletion are eliminated.
*Peripheral tolerance is a sweeping mechanism for elimination of self-reactive B and T cells which escaped central tolerance.
*Tolerogenic strategies consist of cellular therapies total lymphoid elimination protocols with irradiation of thymus, spleen and lymph nodes, and blocking of costimulatory pathways, Belatacept.
*Microchimerism is the presence of a small number of donor cell within the recipient body without inducing immunological reaction.
*A good instance of tolerogenic protocol that uses stem cell infusion to achieve a state of mixed chimerism.
A tissue or organ surviving in a foreign host without immunosuppression defines tolerance.
A well-functioning graft without histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host defines Clinical Operational tolerance.
lack of immune reaction towards the allo-graft in absence of immunosuppression defines Immunological tolerance which means that the allo-graft is accepted by the immune system.
Self-tolerance means that our immune system can recognize self from non-self-tissue and subsequently prevent harmful autoreactive lymphocytes.
Elimination of potentially auto reactive lymphocytes via clonal deletion defines central tolerance.
Thymocytes (double positive cells) are the mature T-cells after incorporating the CD4 and CD8 antigens in addition to T-cell receptor.
These Thymocytes react with the self peripheral proteins which are represented as peptides in the thymic stroma.
Cells that react strongly will be removed by apoptosis, process called negative selection.the favourably reacting cells become mature T-cells that express either CD4 or CD8 receptor (single positive T cell)—–à Clonal Selection process.
3-5% of the original T-cells are positively selected and leave the thymus gland as a mature T-cells.
B-cells will have maturation in the bone marrow via the B cell receptor.
Self reactive T-cells and B-cells that escaped central tolerance into the peripheral circulation will be destroyed by on of the following mechanisms:
Deletion and Apoptosis: AICD
Anergy: Hyporesponsiveness of Tor B-cells.
Regulation or Suppression: natural and adaptive T-reg cells
Thymus derived T-reg –à central immune tolerance.
Peripherally derived T-reg—–àperipheral immune tolerance.
In vitro induced T-reg cells.
Chimerism: Co-existence of donor and host hematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Microchimerism means persistence of a small number of donor cells within the recipient body which can lead to spontaneous operational tolerance in 20 % of liver transplant.
Tolerogenic strategies:
A- Cellular Therapies.
B- Total Lymphoid elimination protocols.
C- Splenectomy.
Cellular therapies in use to induce tolerance:
1- T-cell depletion: using ATG, Alemtuzumab.
2- Co-stimulation blockade: using Abatacept, belatacept or Efalizumab.
3- Other T-cell therapies: Bailiximab, Aldesleukin+Rapamycin.
4- B-cell therapies: Rituximab, Belimumab, Atacicept, Bortezomib, Eculizumab.
Total Lymphoid elimination protocol: Irradiating lymph nodes, spleen, and thymus. Limited to use in patients with MM and ESRD to induce a state of lympho-hematopoietic chimerism.
Splenectomy: was used in Japan for ABO incompatible transplants because spleen produces B-lymphocytes and IgM
The available protocols for inducing tolerance have significant drawbacks in terms of drug toxicity and unpredictable results
Tolerance means well functioning allograft in the absence of exogenous immunosuppression and having intact immune system it’s achieved by controlling T cells reactivity in both central and peripheral .
Partial tolerance also used to describe that when the recipient is using minimal dose of immunosuppression after induction using alemtuzumab.
Central tolerance means eliminating T cells reactivity against Ag (donor Ag) through thymus which will cause deleted of developing T cells coronal deletion ,reaching a state that both donor and recipient cells are present (chimerism) but this need active healthy thymus
Peripheral tolerance by using self tolerance T cells that are escaped from central tolerance will be detected and deleted by peripheral tolerance through various mechanisms
Outcome of transplantation has improved in recent years using patient immunosuppression medications. Immunosuppressant drugs have adverse effects such as infections or malignancy. So, the ultimate goal in transplantation is tolerance. It means survival of a donor organ in recipient’s body with no immunosuppression. Self-tolerance means no attack to self-antigens. That is achieved by central tolerance and peripheral tolerance. Central tolerance happens in thymus during T-cell development and is done by clonal deletion, anergy or receptor-edition. But some of auto reaction T cell can still be present in the periphery and are handled by peripheral tolerance. In addition to T REG and B REG cells, anergy and apoptosis are different mechanisms of peripheral tolerance. T REG cells are usually CD4+, CD25+ and FOXP3positive.A subset of T reg cells are CD4+, FOXP3- type1 regulatory T (Tr1) cells that have immunomodulatory effects which attracts attention. Different tolerance signatures or biomarkers are identified. Robello-Mesa et al.validated a gene expression signature and Brouard et al. Identified a score based on six genes and two demographic variable that was associated with de novo DSA. Multicenter study conducted by Lechler et al.in 71 KT patients with sex and age matched control showed five characteristics of tolerant persons.
Microchimersim means presence of a few donor cell with in the recipient circulation. Chimerism means presence of donor and recipient’s stem cells without a reaction. Different tolerance inducing strategies are tried including cell therapies, lymphoid elimination protocols, costimulatory signal blockage and even splenectomy. Tolerance protocols at MGH and Stanford used mixed chimerism strategies whereas protocols at Johns Hopkins and Northweetaren utilize full-chimerism strategies.
Transplantation tolerance is a state in which the immune system of the recipient of a tissue or
organ transplantation does not attack the
transplanted tissue. Transplantation tolerance is induced by immunosuppression, and prevents rejection of the transplant.
Clinical operational tolerance” is described as a well-functioning graft with out histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other problems including infections
Immunological tolerance” is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specifi c immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
Self-tolerance refers to the ability of the immune system to recognize—and therefore not respond against—self-produced antigens. If the immune system loses this ability, the body can start to attack its own cells, which may cause an autoimmune disease
central tolerance in the thymus and peripheral tolerance in extrathymic lymphoid tissue
Microchimerism is persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. can occur from pregnancy, blood transfusion and previous transplants.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerogenic strategies
1-Cellular therapies:
2-Total lymphoid elimination protocols
3-Splenectomy
Current tolerogenic strategies in use.
*Strategy T cell depletion ATG: T-cell depletion in blood and peripheral lymphoid tissues
and Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
*Costimulation blockade Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
*Other T cell therapies Basiliximab: Blockade of CD25
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 cell therapies
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Tolerance is important goal because transplant recipients are subjected to global immunosuppression that leaves them at increased risk for infections and malignancies. In addition, current chronic immunosuppression regimens do not guarantee indefinite or even excellent long-term allograft
☆ Tolerance us presence of foreign organ in a host with no need of immunosuppression.
Clinical operational tolerance is no histological finding of rejection of well-performed graft in an immunocompetent host without need of immunosuppressive for a year at least.
Immunological tolerance is no immune responses against allograft without immunosuppressives. The immune system of host accepts the graft in non-appearance of immunosuppression.
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☆ Self-tolerance
It is a type of monitoring system to kill and stop any expansion of harmful T and B cells.
It is consist of central and peripheral tolerance.
T and B lymphocytes mature in the thymus and bone marrow where they learn to differentiate between self-antigen and non-self antigen.
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☆ Central tolerance
It is elimination of potentially auto-reactive T and B cells by clonal deletion.
Mechanism: angery, deletion or receptor editing.
T cells reach the thymus to mature. They are called double negative as they lack CD4 and CD8. During maturation, they have CD4 and CD8 so are called double positive thymocytes.
• Negative selection is elimination of T cells which react strongly with self-peptides.
• Colnal selection is maturation of single positive T cells which react with self-peptides and express either CD4 or CD8.
T cells are tested for reactivity before leaving the thymus. Positive selection and maturation of T cells occur to only 3-5 % of original T cells.
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☆ Peripheral tolerance
Sweeping system that destroys the self-reactive T and B cells in peripheral circulation as they are not damaged by central tolerance mechanism.
Mechanism: deletion and apoptosis, angery and regulation or suppression.
Tr1 cells are subtype of pTreg cell and have immunomodulatory functions ,so they are target for tolerance.
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☆ Tolerance signatures
Spontaneous tolerance, which was first reported in 1975, was achieved by chance in non-adherant patients.
Thera are biomarkers for tolerance signature and several studies showed that tolerant patients have the same findings such as:
• lack of DSA.
• fewer activated CD4+ Tcells.
• expansion of peripheral blood B lymphocytes.
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☆ Chimerism
The host accepts donor haematopoitic stem cells without stimulating immunological system against the donor cells.
Exposure to foreign antigens in uteto may lead to microchimerism and therefore acquired tolerance.(Owen et al 1945)
Microchimerism is presence of donor cells within the recipient (< 1% of all circulating recipient cells). It developes due to pregnancy, previous blood transfusion or transplantation. It leads to spontaneous operational tolerance.
Dizygotic twins (HLA non-identical) show incomplete microchimerism and therefore inadequate tolerance.
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☆ Tolerogenic strategies
• Current tolerogenic strategies in use
ATG, Alemtuzmab, Abatacept, Basilixmab,
Rituximab, Bortezomib,and Eculizumab.
• Current cellular therapies in development
Mixed chimerism, Regulatory T cell,
Regulatory B cells and myeloid derived
suppressor cell.
• Total lymphoid elimination protocol
Irradiation of LNs, spleen and thymus.
Limited use in clinical practice.
Used in multiple myeloma with ESRD.
• Splenectomy
Results in elimination of B lymphocytes and
IgM and leads to tolerance
Used in Japan in ABO incompatible
transplantation resulting in higher rate of
graft survival.
Other studies show that spleen is essential
for self- tolerance through maintenance of
regulatory T cells.
There are many successful protocols aiming to achieving tolerance in kidney transplantation and stoppage of immunosuppressive theray through full chimerism , transient or permanent mixed chimerism.
Good
References?
Rathore R, Gunawansa N, Sharma A, Halawa A (2017) Current State of Tolerance: The Holy Grail. Arch Clin Nephrol 3(2): 057-063. DOI: http://dx.doi.org/10.17352/acn.000028
Summary of Tolerance
-ability of foreign tissue or organ to survive in host without immunosuppression
-Clinical operations tolerance – functioning graft without histological evidence of rejection in the absence of IS for at least 1 year in immunocompetent host capable of responding to lather challenges including infections
-immunological tolerance – no detectable immune reaction towards allograft in the absence of IS.
Self tolerance
-lymphoid system comprises T and B lymphocytes which controls the immunity protecting the host from foreign pathogens
-T cell and B cell undergo education and maturation proceed in the central lymphoid organs
Central Tolerance
-affinity-avidity model- self tolerance divided into central and peripheral tolerance – prevent expansion of potential harmful auto-reactive T and B cell clones
-intermediate affinity – self reactive T cells with intermediate affinity / avidity for self antigens that escape thymic negative selection and released into periphery, display lower affinity for MHC/self peptide complexes but capable of self peptide driven profile ration and may differentiate into effector cells
-central tolerance is most important -clonal deletion, eliminate auto-reactive T and B cell
-T and B cell mature in thymus and BM
-T cells first reach the thymus – immature and lack of TCR and lack of CD4 /CD8 antigens (double negative)
-TCR incorporated and uporegulation of CD4/8 antigens in thymus
-double positive cells – starts ewcting to self peripheral proteins in thymic stroma
-self peptides that strongly react with T cell – eliminated by apoptosis ( negative selection)
-cells that react favourably will mature either CD4/CD8- clonal selection
-thymocytes with low affinity -die within thymus
-B cells -immature -in bone marrow through the B cell receptor
Peripheral Tolerance
-destroying self reactive T and B cells that escaped central tolerance mechanism and circulating in peripheral
-controlled by one of process: deletion, apoptosis, energy and regulation or suppression
-tTreg – main mediators of central immune tolerance
-pTreg – regulate peripheral immune tolerance
-iTreg – in vitro induced Treg cells
Mechanism of central tolerance
Step 1: Anergy- If signalling through the BCR is sufficiently weak, immature B cells becomes unresponsive forever
Step 2: Deletion- If immature B cells are strongly self-reactive -deleted
Step 3: Receptor editing- Through BCR gene rearrangements, a new receptor with altered specificity is generated
Mechanism of peripheral tolerance
Deletion and apoptosis/activation-induced cell death (AICD): mediated by interaction of Fas (CD95) with its ligand (Fas-L or CD95L) on T cells
– can occur in developing thymocytes as well as mature T cells.
Anergy: state of hyporesponsiveness of T or B cells to antigenic stimulation. Can be result from antigenic stimulation in the absence of costimulation.
Regulation or suppression: Treg cells consists of “natural” Treg and “adaptive” Treg. They control immune response to a foreign antigen whilst ensuring that the host remains undamaged
Foxp3, pTreg and iTreg expressed in cells depends on stably-divided into 2 subsets
-Calssical CD3+Foxp3+Treg
-CD4+Foxp3-type 1 regulatory T (Tr1) cells – have been recognised for immunomodulatory
Functions – make a them promising target for prevention of organ transplant rejection
Tolerance signatures
-help in formulating predictive models for identifying those recipient that will achieve tolerance with minimal or IS free in long run
Tolerant patients showed the following characteristics
• expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of donor specific antibodies
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene
expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism
Chimerism – co-existence of donor and host haematopoietic stem cells inside the host without stimulating immunological reaction against donor cells
Transplantation between genetically identical monozygotic twins – shown results of tolerance
-Dizygotic twins- microchimerism -leads to inadequate tolerance
Microchimerism – persistence of <1% of all circulating recipient cells within the recipient body c
-occur from pregnancy, blood transfusion and previous transplants.
Tolerogenic strategies
• Cellular therapies
• Total lymphoid elimination protocols
• Splenectomy
Current tolerogenic strategies in use
Strategy
T cell depletion
Mechanism of action
• 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
• Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes
Costimulation blockade
• Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway
• Efalizumab: Blockade of LFA-1:ICAM-1 co-stimulatory pathway
Other T cell therapies
• Basiliximab: Blockade of CD25
• Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival and stabilise the expression of FoxP3
B cell therapies
• Atacicept: Blockade of BAFF and APRIL (A proliferation inducing ligand)
• Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
• Eculizumab: Blockade of complement protein C5 to prevent complement mediated injury
Current Cellular therapies still in research
Mixed chimerism
Infusion of donor bone marrow into myoablated /immune-conditioned recipient for producing co-existence of donor and recipient cells
Regulatory T cells
Infusion of expanded regulatory T cells to inhibit inflammatory cytokine production, down-regulate costimulatory and adhesion molecules, promote anergy and cell death, convert effector T cells to a regulatory phenotype and produce suppressive cytokines IL- 10,TGF-B and IL35
Dendritic cells
Deletion of T cells, induction of Tregs and anergic T cells, expression of immunomodulatory molecules and immunosuppressive factors
Macrophages
Enrichment of CD4+ CD25+ Foxp3 cells and cell contact and casp ase dependent depletion of activated T cells
Myeloid derived suppressor cell
Inhibit proliferation of effector T cells, activate inhibitory T cell receptors and inhibit IFN-Y producing T cells
Mesenchymal stromal cells
Inhibition of T cell activation and proliferation by upregulation of FoxP3 regulatory T cells and downregulation of MHC Class II and co- stimulatory molecules
Regulatory B cells
Maintenance of CD4+FoxP3+ regulatory T cells, production of TGF-B, IL-35, IgM, expression of Fas-L
Well done
Tolerance is the dream of every doctor in the transplantation team. simply it defined as graft survival without immunosuppression with no rejection.
Central tolerance for T lymphocytes is done in the thymus where autoreactive T cell is eliminated by process called negative selection. Peripheral tolerance in which peripheral derived T lymphocytes can suppress the inflammation.
Tolerance signatures is an important subject , and Knowing which from our patients developed graft tolerance is of critical importance to allow reduction of immunosuppressive drugs. Till now no single marker had been agreed as marker of tolerance, several markers had been suggested but still as experimental markers.
Chimerism is the presence of hematopoietic stem cells from the donor and recipient without occurrence of graft rejection. in this way we can induce tolerance for the graft. it used in many protocols to induce tolerance.
Strategies to induce tolerance :
Cellular strategies: This strategies uses hematopoietic stem cell from the donor to induce tolerance . Various protocols had been suggested with different conditioning regimes with different results . One strategy called Facilitated Cell Infusion had good results.
Total lymphoid irradiation strategy: it uses irradiation of the spleen, thymus and lymph nodes . this strategy had high level of toxicity, and it’s use is limited to certain patients with multiple myeloma and renal failure.
Spleenectomy : By removing the spleen we can remove a major site of antibody production , and some centers use it for ABO incompatible donors . Some critized this strategy because spleen is also a site of regulatory T cells which are important in tolerance.
Another strategy to induce tolerance is to use various drugs to inhibit T cells and B cells , some of these drugs are in use in clinical practice. These drugs like ATG, Belatacept, Basiliximab, Rituximab ,Bortezomib, Belimumab and Atacicept.
One last question
Have we achieved tolerance or near tolerance (transplantation survived on minimal immunosuppression)?
Not really prof although partial tolerance have been reported in setting of non-adherence in renal transplantation. some success in animal models but in human not yet.
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
Clinical operational tolerance is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
Immunological tolerance is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
T cells and B cells undergo education and maturation in the central lymphoid organs. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens.
self-tolerance comprises of central and peripheral tolerance and can be described as a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones.
Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion.
Peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that in some way escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Transplantation between genetically identical monozygotic twins has shown remarkable results of tolerance However, among dizygotic (HLA non-identical) twins, the microchimerism is incomplete and hence leads to inadequate tolerance.
Microchimerism is persistence of a small number of donor cells within the recipient body, this can occur in pregnancy, blood transfusion and previous transplant.
Strategies to induce Tolerance
Total lymphoid elimination protocols: by irradiating the lymph nodes, spleen and thymus. 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.
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 transplants. some recent studies have shown that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance.
ATG: T-cell depletion in blood and peripheral lymphoid tissues
Alemtuzumab: Depleting monoclonal antibody to CD52 on T,B,NK cells and monocytes.
Costimulation blockade: Abatacept, Belatacept: Blockade of CD28:CD80/86 costimulatory pathway.
Basiliximab: Blockade of CD25 Aldesleukin + Rapamycin: Increase regulatory T cell proliferation and survival
B cell therapies Rituximab: Depleting monoclonal antibody to CD20
Belimumab: Blockade of BAFF B cell activating factor causing depletion of follicular and alloreactive B cells.
Bortezomib: Proteosome inhibitor causing apoptosis of mature plasma cells
Eculizumab: a long-acting humanized monoclonal antibody targeted against It inhibits the cleavage of C5 into C5a and C5b and hence inhibits deployment of the terminal complement system including the formation of MAC.
Excellent, well done.
I will quote this paragraph from your answer” 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 transplants. some recent studies have shown that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance”
Tolerance is the capability of a transplanted organ in our sense to survive in the host without immune suppression. this could be clinical showing good histological findings or immunological shown by no immune activity against donor’s organ.
t cells play a key role. after maturing and presenting cd4/cd8 positivity, the T cells that are not consistent with self are eliminated by negative clonal selection. cells that escape this central selection are swept peripherally. tolerance signatures drew attention since the 1970s. In 2010, Lechler et al. published their paper showing some characteristics of tolerant patients mainly with absent DSAs and fewer CD4+ cells. many tolerogenic strategies are applied. mainly ATG repletion of lymphocytes, monoclonal antibodies like belatacept and basiliximab in addition to B cell depletion by rituximab are used.
chimerism first studied in bone marrow transplantation is also studied and used for renal transplant patients especially in patients with malignancy with promising results. Massachusetts General Hospital protocol (MGH) had some protocols. either full sustained or transient full immune impression withdrawal was not attained except around 50 of cases (mean ). still, we need to understand the complex immune system. this is the big challenge
Excellent, well done.
Tolerance is the ability of foreign tissue or organ to survive in a host without immunosuppression.
Self tolerance: the ability of B & T cells to differentiate between self and non self antigens.
Central tolerance: is the process by which the potentially autoreactive T & B cells are eliminated by clonal deletion.
Peripheral tolerance: the mechanism of destroying self reactive T & B cells that escape the central tolerance and end up in the peripheral circulation.
Chimerism: co-existence of donor and host hematopoietic stem cells inside the host without inducing immunological reaction against donor cells.
Microchimerism: the persistence of a small number of donor cells within the recipient body, this can occur in pregnancy, blood transfusion and previous transplant.
Tolerogenic strategies:
Cellular therapies: different cellular therapies in development, knowledge of their mechanisms of action is still under development
Total lymphoid elimination protocols: total irradiation of lymph nodes, spleen and thymus. clinical application is limited due to toxicity.
splenectomy: previously used for ABO incompatible transplantation.
currently the following strategies are used:
Achieving tolerance in transplantation is still a challenge, the proposed protocols for inducing tolerance have significant complications due to drug toxicities and the unpredictable results. cellular therapies appear to be promising.
Excellent, well done.
Tolerance is the acceptance of allograft in the recipient without immunosuppression.
Self tolerance:
Central tolerance:
Peripheral tolerance:
Tolerance signature:
Characteristics of tolerant patients was shown by a multicenter study included:
Chimerism:
Current tolerogenic therapies in use:
T cell depletion:
Costimulation blockade:
Other T cell therapies:
B cell therapies:
Current cellular therapies in development:
Splenectomy:
stops production of B lymphocytes & IgM, used in ABO incompatible transplant
leads to high rate of graft survival
limited as recent studies showed that spleen is important for induction of regulatory T cells that are important for self tolerance
Total lymphoid elimination:
irradiation of lymph nodes, spleen & thymus
highly toxic
used only in multiple myeloma with end stage renal disease to induce lymphohematopoietic chimerism.
Excellent, well done.
TOLEARNCE MEANS TO ADAPT .
since transplantions started, our aim that the kidney graft not be rejected, and the recipent can tolerate or adapte with this foreign antigens.
types of toleance
a-Self tolerance is defined as the ability of B and T lymphocytes to maturate differentiating between self and foreign antigens therefore not attacking self antigens
b-Central tolerance
a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion
c-peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis,
energy, and regulation or suppression
stratiges to achive tolearnce in recipent
1- Total lymphoid irradiation ( thymus, lymph nodes, spleen) , high risk of infections.
2- Splenectomy in ABO incompatible donor, but spleen is important for regulatory T cells induction and maintenance
3- Costimulation blockade since activation of T Lymphocytes needs that one or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 suppress T cells, this lead to development of Belatacept (a high affenity variant CTLA4-Ig)
4- Donor stem cell infusions to develop chimerism between donor and recipient using short period of immunosuppression and co-stimulation blockade with excellent results
5- T cell directed therapy
a⦁ Basiliximab that block CD25
b⦁ Aldesleukin + Rapamycin that Increase proliferation of regulatory T cell
6- B cell directed therapy
a⦁ Rituximab that deplete CD20
b⦁ Belimumab that Block BAFF B cell activating factor causing alloreactive Bcell depletion
c⦁ Atacicept: Blockade of BAFF and APRIL (A proliferation inducing
ligand)
d⦁ Bortezomib that produce mature plasma cell apoprosis
e⦁ Eculizumab that block C5 to prevent formation opf MA
Excellent, well done.
Tolerance is the ability of the foreign organ to survive in the body of recipient without any immunosuppression and it is the ultimate goal of managing transplantation without complication of immunosuppressive drugs such as infections and malignancies.
Clinical operational tolerance was described as well-functioning allograft in the absence of histologic evidence of rejection without immunosuppression for at least 1 year when the host is immunocompetent.
Immunological tolerance is defined as no detectable reaction toward allograft antigens in the lack of immunosuppression.
During maturation in lymphoid tissues, T and B cells learn to differentiate between self-antigens (self-tolerance) and non-self (foreign antigens).
Self-tolerance consists of central and peripheral tolerance. Central tolerance is the most important process by which autoreactive T-cells and B-cells by clonal deletion are eliminated. During the maturation process, in thymus, T cells undergo a rearrangement process and form double positive T cells (have both CD4 and CD8). Then if these cells react too strongly with self-peptides will be eliminated by apoptosis (negative selection) and those with favorable reaction with self-peptides undergo positive selection and form single positive T cells (have CD4 or CD8). The process of negative selection is true for B cells in bone marrow as well. Peripheral tolerance is a sweeping mechanism for elimination of self-reactive B and T cells which escaped central tolerance. Mechanisms of central tolerance are anergy, deletion and receptor editing; and the mechanisms of peripheral tolerance are deletion and apoptosis, anergy and regulation or suppression. Thymus Treg cells are considered the main mediators of central tolerance and peripheral Treg cells are the main regulators of peripheral immune tolerance. Tr1 cells are the promising target for the prevention of transplant rejection.
In one study, tolerant patients have special characteristic including: expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, lack of donor specific antibodies, donor specific hyporesponsiveness of CD4+ T cells, high ratio of FoxP3 to α-1,2 mannosidase gene expression, differential expression of B cell related genes and associated molecular pathways.
Microchimerism is the persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body without inducing immunological reaction that can lead to spontaneous operational tolerance as is seen in 20% of liver transplantation.
Tolerogenic strategies consist of cellular therapies (such as mixed chimerism, stem cell infusion, infusion of Treg and B reg cell, dendritic and macrophage cells, …), total lymphoid elimination protocols with irradiation of thymus, spleen and lymph nodes, splenectomy, and blocking of costimulatory pathways with different agents such as CTLA4Ig, Belatacept; which of them have special limitations and applications.
One of the best examples of tolerogenic protocol is MGH protocol that uses stem cell infusion to achieve a state of mixed chimerism. This protocol uses T cell modulation and co stimulation blockade with short term immunosuppression without myeloablation. This model is evident of central tolerance with excellent allograft survival.
Excellent, well done.
Transplantation Tolerance :referes to the ability of the transplanted gragft to survive in the immunocompetant recipient without using immunesuppressive drugs (Immunogenic tolerance) and in Abecense of histological signs of rejection for 1 year at least (Clinical operational tolerance ). It was first described in expremental model in 1950 and since then ongoing efforts are exerted trying to identify biomarkers for tolerance that can be applied clinically to identify tolerant recipients , in whom the graft can survive with minimal immunesuppression .
Tolerant patients are characterized by
1- Absent of DSA
2- Increased number of prepheral blood B and NK cells
3- Few activated CD4+ T cells with hyporesposeviness to DSA
4- high ratio of FoxP3 to α-1,2 mannosidase gene expression
5- different expression of B cell related genes and molecular pathways
Chimerism, refres to presence of some of the donor heamatopiotic stem cells in the recipient without inducing immune response against these donor cells , representing a state acquired tolerance that results from exposure to non self antigens during early life or from blood transfusion , pregnancy and previous transplantation .
Therapeutic strategies aiming at achieving tolerance include
1- Elimination of the whole lymphoid tidssue through irradiating spleen , LNs and thymus . But this is associated with serious complications , thus it is only preserved for MM associated with ESRD.
2- Splenectomy or Splenic irradiation to eliminate B lymphocytes and IgM.
3- T cell depletion through either ATG or Alemtuzumab Or Blockage by Basiliximab
4- Blocking the costimulatory signals for T cell activation leading to T cell anergy via Abatacept, Belatacept , falizumab
5- B cell directed therapy as
a- CD20 depleting monoclonal antibody as Rituximab
b- depletion of follicular and allore active B cells via blocking BAFF B cell activating factor as Belimumab and Atacicept
c- Proteosome inhibitor leading to apoptosis of mature plasma cell as Bortezomib
d- Blocking complement activation via blocking of complement protein C5 as Eculizumab
Excellent, well done.
Despite advances in organ transplantation with advances in immunosuppression , but still immunosuppression has major side effects mainly infections and malignancy that affects patients survival .
Understanding complicated and organized functions of immune system is the starting point to reach the goal of achieving clinical or operational tolerance long term in renal transplant recipients in the absence of immunosuppression .
Tolerance ; is the ability of a foreign tissue or organ to survive in a host without immunosuppression as the host can’t recognise the foreign orange as non self so it doesn’t initiate immunresponce to it and it’s describedas a state of donor specific non-reactivity.
Clinical operational tolerance ; is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections.
Immunological tolerance ;is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specific immunological acceptance of the allograft by the host immune system in the absence of immunosuppression.
Self-tolerance; in our early life with
development of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens this is done in 2 steps central and peripheral to ensure elimination of harmful auto-reactive T and B cell clones this process is called clonal deletion .
In the thymus T cells is incorporated with TCR
with upregulation of CD4 and CD8 on its surface and it’s called double positive TCells or thymocytes
which starts to react with thymic peptide representing self antigen are deleted by apoptosis
While 3-5 % of T cells that entered the thymus and had favourable reaction with self peptides become mature released with either CD4 or CD8 receptors and so called single positive T cells.
B cells are also tested for reactivity to self-antigens before they enter the periphery. Immature B cells, developing in the bone marrow, test antigen through the B cell receptor.
Peripheral tolerance
Some T and B cells can escape to peripheral circulation and can later become potentially pathogenic effector cells.
Peripheral tolerance; it is a mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis, energy, and regulation or suppression.
Thymus-derived regulatory T (tTreg) cells are considered main mediators of central immune tolerance, whereas peripherally derived regulatory T (pTreg) cells function to regulate peripheral immune tolerance. third type of Treg cells, termed iT reg, represents only the in vitro-induced T reg cells.
pTreg, and iT reg cells may be divided into two subsets:
* Classical CD4+Foxp3+ T reg cells and
* CD4+Foxp3− type 1 regulatory T (Tr1) cells.
Peripherally derived regulatory T ) cell subset (Treg CD4+Foxp3− type 1 regulatory T (Tr1) cells have immunomodulatory functions which may be promising in prevention of organ rejection.
The suppressive function of Tregs relies heavily on high and stable expression of the transcription factor FOXP3, which, together with other transcription factors, activates anti-inflammatory genes and represses proinflammatory genes.
transcription factor Foxp3 is critically important for the development and function of Tregs. Foxp3 not only can keep the cells on right developmental tracks toward a suppressive phenotype, but also seems to be a prerequisite to for stabilizing the Treg lineage . Furthermore, loss of Foxp3 expression over time impairs the suppressive activity of Tregs (1).
Tolerance signatures; it was found that some non transplanted patients are not adherant to immunosuppression and they didn’t reject the foreign oragan.
Tolerant patients showed the following characteristics :
• expansion of peripheral blood B and NK lymphocytes
•fewer activated CD4+ T cells
•lack of donor specific antibodies
•donor specific hyporesponsiveness of CD4+ T cells
•high ratio of FoxP3 to α-1,2 mannosidase gene expression
•differential expression of B cell related genes and associated molecular pathways
Chimerism
It’s the presence of both donor and host haematopoietic stem cells inside the host without causing immunological reaction against donor cells.
Microchimerism
It is the persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. Presence of such microchimerism can occur from pregnancy, blood transfusion and previous transplants.
Microchimerism leads to spontaneous operational tolerance has been seen in up to 20% of liver transplants thought to be due to large number of donor leukocytes that come with the transplanted liver and lead to donor microchimerism in the recipient.
Tolerogenic strategies ;
•Cellular therapy
Using different kinds of cells which may be doner bone marrow cells to induce chimirism ,T reg cell to modulate the immune response and produce Anergy , other types of cells sush as dentiritic , macrophages,regulatory B cells all are studied to modulate immune system and induce tolarance .
•Total lymphoid elimination protocols:
using irradiating the lymph nodes, spleen and thymus this highly toxic and not used in practice to all patients but can be limited to multiple myeloma patients and co-existing end stage renal failure to induce a state of lympho-haematopoietic chimerism.
•Splenectomy: Spleen produces B lymphocytes and IgM. Splenic irradiation or splenectomy results in elimination of these antibodies resulting in a state of tolerance but the main drawback is that spleen is important for induction and maintenance of regulatory CD4+CD25+ T cells which in turn are important for self-tolerance.
There are some current strategies in use to achieve tolerance:
* T cell depletion with induction of T reg using ATG
* depleting monoclonal Ab to CD 52 on T ,B And NK cells and monocytes by Alemtuzumab
And basiliximab blocking of CD 25 .
* blocking co stimulation pathways using balatacept and abatacept.
* B cell therapy using rituximab monoclonal Ab to block CD 20 .
1 Fontenot JD, Gavin MA, Ruensky AY. Foxp3 programs the evelopment an function of CD4+CD25+ regulatory T cells. Nat Immunol (2003) 4:330–6.
Excellent, well done.
Tolerance is the survival of graft without using any immunosuppressive medicines.
It has many aspects: clinical one, denoting graft function without immunosuppressive and immunological one, referring to undetectable antibodies against donor antigens.
Selftolerance is a natural mechanism of differentiating between one own antigen and foreign ones.
Another important term is Chimersim denoting having both host and donor stem cells without evoking the immune system.
Tolerance is still unmet need in transplantation.
Tolerance
refers to a foreign tissue or organ’s ability to survive in a host without being immunosuppressed.
it can be described as donor-specific non-reactivity.
In the absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges such as infections, “clinical operational tolerance” is defined as a well-functioning graft with no histological evidence of rejection in the absence of immunosuppression.
Self-tolerance
T and B lymphocytes make up the lymphoid system, which regulates the immune system and protects the host from external diseases.
T cells and B cells are educated and matured in the key lymphoid organs, the thymus and bone marrow, throughout the lymphoid system’s developmental process. T and B lymphocytes learn to distinguish between self-antigens and non-self (foreign) antigens throughout this maturation phase.
Tolerance in the centre
Self-tolerance, which includes both central and peripheral tolerance in the affinity-avidity model, can be thought of as a kind of surveillance mechanism that prevents the spread of potentially harmful auto-reactive T and B cell clones.
Self-reactive T cells with intermediate affinity/avidity for self-antigens that survive thymic negative selection and are discharged into the periphery are referred to as intermediate affinity.
The most essential method by which potentially auto-reactive T and B cells are removed is central tolerance, which is achieved by a process known as clonal deletion.
Peripheral tolerance
is a cleaner mechanism that kills self-reactive T and B cells that have gotten past the central tolerance system and are now floating about in the bloodstream. They are regulated or suppressed by one of the following processes in the periphery: deletion and apoptosis, energy, and regulation or suppression.
CD4+Foxp3 type 1 regulatory T (Tr1) cells, a peripherally derived regulatory T (Treg) cell subgroup, have garnered growing attention for their immunomodulatory properties, making them a prospective target for organ transplant rejection prevention.
Definitions
⦁ Tolerance is surviving of foreign tissue or organ without immunosuppression
⦁ Immunological tolerance is the absence of immune response to a foreign tissue or organ
⦁ Clinical tolerance means that in an immunocompetent patient without immunosuppression for 1 y, the graft is clinically stable with no signs of rejection.
⦁ Self tolerance the ability to identify self antigens as self by T and B lymphocytes
⦁ Chimerism is the absence of immunological reaction between donor and recipient stem cells
⦁ Microchimerism is presence of few donor cells < 1% of recipient cells in the recipient circulation due to previous sensitization from pregnancy, previous transplant and blood transfusion
Mechanism of tolerance
– CD4 + Foxp3+ Treg cells
– CD4 + Foxp3 – type 1 regulatory T (Tr1) cells (may be a target for tolerance)
Criteria of tolerant patient (tolerance signature)
⦁ Increase in peripheral blood B and NK lymphocytes and decrease activated CD4+ T cells with hypo responsiveness to donor cells
⦁ Absence of DSA
⦁ Ratio of FoxP3 to α-1,2 mannosidase gene expression is high
⦁ Expression of B cell related genes
Strategies for induction of tolerance
1- Total lymphoid irradiation ( thymus, lymph nodes, spleen) in multiple myloma associated with ESRD, but there is very high risk of infection using this therapy
2- Splenectomy in ABO incompatible donor, but spleen is important for regulatory T cells induction and maintenance
3- Costimulation blockade since activation of T Lymphocytes needs that one or more TCR antigens (CD28, CTLA-4) interacts with its specific legend in APC (B7-1, B7-2). this is called costimulation, CD28 stimulate, while CTLA-4 suppress T cells, this lead to development of Belatacept (a high affenity variant CTLA4-Ig)
4- Donor stem cell infusions to develop chimerism between donor and recipient using short period of immunosuppression and co-stimulation blockade with excellent results
5- T cell directed therapy
⦁ Basiliximab that block CD25
⦁ Aldesleukin + Rapamycin that Increase proliferation of regulatory T cell
6- B cell directed therapy
⦁ Rituximab that deplete CD20
⦁ Belimumab that Block BAFF B cell activating factor causing alloreactive Bcell depletion
⦁ Atacicept: Blockade of BAFF and APRIL (A proliferation inducing
⦁ ligand)
⦁ Bortezomib that produce mature plasma cell apoprosis
⦁ Eculizumab that block C5 to prevent formation opf MAC
Well done; thank you
What is meant by tolerance in your own words?
Have we managed to achieve tolerance?
tolerance means body recognize renal allograft as self not non self , so no immunosuppression needed and no rejection attacks.
still reaching tolerance is under research.
What are your thoughts about bone marrow and kidney transplantation for patients with multiple myeloma? Do you think this is a tolerogenic strategy? Have you ever heard about such trials?
As in the review (Published online 2016 Apr 30. DOI: 10.1155/2016/6471901
Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance written by : Yi-Bin Chen, Tatsuo Kawai, and Thomas R. Spitzer ) it was proposed to be of benefit to do BMT several months after Kidney Tx). It may have promise but I think we need to set the protocols before applying this risky procedures in otherwise healthy patients (namely who only need kidney tx).
I came across with middle-aged women but I could not remember the matching of her donor. she left all medications abruptly and came late to transplant center I visited 6 years ago and I was told she is one of about 50 (maybe 15) in the world. samples of her blood were sent to European research center. Still, we need research about tolerance and mechanisms of achievements to lower risk of unnecessary high doses of immune suppression
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Tolerance could be achieved by irradiating central and peripheral lymphatic systems including lymph nodes, spleen and thymus. The high toxicity of this approach has limited it clinical use. However, patients with hematologic malignancies, and in particular patients with multiple myeloma and co-existing end stage renal failure, immunological tolerance to a renal allograft after having previously received a hematopoietic stem cell transplant from the same donor was attempted.
But does is approach worth? In real life, continuous immunosuppression puts transplant recipients at risk of severe infections, malignancies, increased cardiovascular morbidity and mortality, and drug related side effects like de novo diabetes, dyslipidemia.
One of the fundamental challenges of tolerance-inducing protocols is to identify those patients in which the protocol was successful and which can, thus, safely be weaned off immunosuppression. Stable multi-lineage chimerism has long been regarded as the most robust predictor for tolerance and donor T cell engraftment in particular as a critical parameter.
The feasibility and safety of this approach have been well established. There has been no transplant-related mortality, few developed acute graft versus host disease (GVHD).
Combined bone marrow and kidney transplantation was feasible and that mixed or full donor chimerism, either transient or sustained, could result in long-term renal allograft acceptance without, in some cases, systemic immunosuppression.
The broader application of tolerance induction strategies, however, is for patients with organ failure and without an underlying malignancy to avoid the deleterious effects of lifelong immunosuppressive therapy still under evaluation taking into account that GVHD is not an acceptable complication in this patient population and could end with death.
Advances in Hematology Volume 2016, Article ID 6471901, 8 pages http://dx.doi.org/10.1155/2016/6471901
There are limited data about bone marrow and kidney transplantation fo MM patients but as mentioned in this article
findings on 10 patients who received combined bone marrow and kidney transplants from HLA single haplotype mismatched living donors. Transient chimerism developed in all recipients and tolerance to donor alloantigens was achieved in majority of patients.
6 patients could not be withdrawn from immunosuppression indefinitely and role of T regulatory cells in development of tolerance was demonstrated.
The time between ASCT and renal transplantation and medications used affected the out come
Optimal treatment of MM consisting of anti-myeloma induction therapy followed by autologous stem cell transplantation (ASCT) and
maintenance therapy is estimated to result in prolonged disease-free remission in 20%. The achievement of complete remission is associated with a 30% chance of non-progression in the following 20 years (1).
only 18 MM patients treated with SCT followed by kidney transplantation have been reported in the literature by Shah et al. Who mentioned that “of our knowledge. Some patients achieved long-term survival without MM relapse and good allograft survival; however, MM relapse, cardiovascular and infectious complications, allograft failure due to rejection and patient death appear to be common in this patient population”.Shah et al.(2)
Also some of induction medications used for MM reported to cause acute kidney injury and graft nephrectomy.
1 Martinez-Lopez J, Blade J, Mateos M-V et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 2011; 118: 529–534.
2 Shah S, Ibrahim M, Delaney M et al. Risk of relapse of multiple myeloma following kidney transplantation: a case series report. Clin Kidney J 2018.
Thank you; much of Hematology perspectives!
Preclinical models of combined kidney and bone marrow transplantation have shown that the tolerance can be achieved through either transient or sustained hematopoietic chimerism.combined transplant in patients with multiple myeloma have shown that organ tolerance and prolonged disease remission can be accomplished with such approach.
Reference:
Chen Y.B., Kawai T.,Spitzer Th.R. Combined Bone Marrow and Kidney Transplantation for the Induction of Specific Tolerance. Advances in Hematology. Volume 2016, Article ID 6471901.
Well done
Check this link; https://www.nejm.org/doi/full/10.1056/NEJMoa074191
This generally good idea, but big challenge is that we not be able to get well matched HLA in kidney transplantation. The success requires high degree of match and that was the case in bone marrow transplantation. The protocol may not be welcomed worldwide due the toxicities associated with conditioning regimens.
Tolerance is the ability of a transplanted organ to stay viable without elicting immune response in an immunocmpetent recipient without the need to use immunosuppresives.
Self tolerance is defined as the ability of B and T lymphocytes to maturate differentiating between self and foreign antigens therefore not attacking self antigens.
Central tolerance is a state where Band T lymphocytes reactive against self antigens are clonaly deleted, this is pursued through anergy, deletion then receptor editing .
Peripheral tolerance is done by destroying self T and B lymphocytes through deletion and apoptosis ,anergy then regulation or suppression.
Thymus derived T regulatory controls central tolerance and periphery derived T reg conrtols peripheral tolerance.
Cells are divided into Classical CD4+Foxp3+ Treg cells and CD4+Foxp3− type 1 regulatory T (Tr1) cells, the later is a target to prevent graft rejection.
Signatures of tolerance revealed expression of B cell–related genes and relative expansions of B cell subsets .
Brouard et al., identified a score based on six genes and two demographic parameters and is not affected by immunosuppression, center of origin, donor type or post-transplant lymphoproliferative disorder history.
Lechler et al ,2010 found that tolerant patients are characterised by increased number of peripheral blood B and NK lymphocytes ,lower number of activated CD4+ T cells , absence of donor specific antibodies and donor specific hyporesponsiveness of CD4+ T cells ,high ratio of FoxP3 to α-1,2 mannosidase gene expression , differential expression of B cell related genes and associated molecular pathways
Chimerism is acquired tolerance ;where host and recipient antigens are existing together without being provocative to recipient immune system.
Monozygotic twin expressed acceptable degree of tolerance while dizygotic expressed insufficient tolerance degree.
Microchimerism was noticed in20% of liver transplantation
Tolerance can be achieved by
-Cellular therapiesare being developed as mixed chimerism , regulatory T cells, Bcells , macrophage , dendritic cells,myeloid derved suppressor cell and mesenchymal stromal cells
-Tcell depletion as ATG , Alemtuzumab ,
-costimulation blockage as Abatacept,
-T cell therpies as Basiliximab,
-B cell therapies as Ritoximb and Balimumab.
-Irradiation to lymph node , spleen and thymus of limited use,
-Splenectomy
Multiple protocols inducing tolerance in kidney transplant recipients was studied to be able to withdraw immunosuppression as those causing full donor chimerism , transient mixed chimerism and sustained mixed chimerism
Concept of tolerance is achieving ultimate goal of a donor organ staying in perfect harmony with recipient body without immunosuppression and with an intact immune system, Tolerance can be immunological tolerance (with no immunological effect on the graft in absence of immunosuppression) or clinical operational tolerance (no histological signs of rejection in absence of immunosuppression for more than 1 year).
Self-tolerance is the concept of ability to prevent proliferation of harmful T or B cells. It can be central or peripheral.
Central tolerance involves destruction of auto-reactive T and B cells by clonal deletion at the central level (Thymus for T cells and Bone marrow for B cells)an immature T cell enters thymus and receives T cell receptor (TCR) and undergoes upregulation of CD4 and CD8 antigen becoming a double positive T cell which reacts with self-peptide. If it shows too strong reaction, it undergoes apoptosis.In presence of a favorable response, T cell matures with either CD4 or CD8 receptor. Central tolerance involves either anergy (poor B cell receptor signalling leading to poorly responding B cells), deletion of self-reacting B cells, or receptor editing (with altered specificity).
Peripheral tolerance involves killing of self-reactive T and B cells (which escape the central tolerance and reach peripheral circulation) by either deletion or apoptosis, anergy (poor response to further antigenic stimulus) or regulation through rregulatory T cells (Treg).
Biomarkers for tolerance (tolerance signatures) have been proposed by various groups and include factors like differential expression of B cell related genes, increased peripheral blood B and NK (Natural Killer) lymphocytes, decreased activated CD4+ T cells, decreased responsiveness of CD4+ T cells, absent DSA, high ratio of FoxP3 to alfa 1,2 mannosidase gene expression etc.
Chimerism is the state of harmonious co-existence of donor and recipient hematopoietic stem cells without any immunological response. Microchimerism is the state of small number of donor cells (less than 1% of all circulating recipeint cells) in the recipient body.
In transplant, tolerance can be achieved at central and peripheral level. Central transplant tolerance can be achieved by destroying the T cell population by methods like total lymphoid irrradiation and donor bone marrow transplant achieving a state of chimerism. Peripheral transplant tolerance can be achieved by using different molecules like ATG (T cell depletion), Abatacept, Belatacept (costimulation blockade), etc. Splenectomy has been used as a method of achieving tolerance by destroying B lymphocytes and IgM antibodies (used in setting of ABO incompatible transplants).
Although progress has been made by following different protocols to achieve tolerance, but their results are still unpredictable and need further refinement.
Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression.
Self-tolerance
In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens
Central tolerance
a kind of surveillance mechanism to prevent expansion of potentially harmful auto-reactive T and B cell clones. Central tolerance is the most important process by which the potentially auto-reactive T and B cells are eliminated by a process called clonal deletion
Peripheral tolerance
Peripheral tolerance is the ‘sweeper’ mechanism of destroying those self-reactive T and B cells that somehow escaped central tolerance mechanism and end up in the peripheral circulation. They are controlled in the periphery by one of the following mechanisms: deletion and apoptosis,
energy, and regulation or suppression
Tolerant patients showed the following characteristics
• expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of donor specific antibodies
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.
Microchimerism is persistence of a small number of donor cells (<1% of all circulating recipient cells) within the recipient body. Presence of such microchimerism can occur from pregnancy, blood transfusion and previous transplants. Microchimerism leading to spontaneous operational tolerance
Tolerogenic strategies
Potential impact of cellular therapies, different cellular therapies are still evolving
At present, proposed protocols for inducing tolerance have significant drawbacks in terms of drug toxicity and unpredictable results. Ongoing trials in cellular therapies by the Transplant Research Immunology Group appear to be promising.
In general tolerance means the absence o fimmune system activation in response to specific antigen. In kidney transplantation, tolerance means the absence of immune response to transplanted graft in the absence of immunosuppression while immune system is intact.
During developmental process of B and T cells in the lymphoid system, education and maturation of these cells occur to finally, be released into the systemic circulation with proper function, preventing by this mean, over-reactive immune cells.
this is achieved by central and peripheral tolerance..
Central tolerance is the process in which only T lymphocytes with favorable function are selected to be released into the circulation, however T lymphocytes with strong reaction to self peptides are eliminated. that why only 3-5 % of lymphocytes entering the thymus are selected for further maturation.
Peripheral tolerance is the second step in eliminating self over-reactive T and B cells that escape from the central tolerance mechanism.
Central and peripheral T regulatory cells are the main cells implicating in the regulation of tolerance.
over the past few decades, a lot of studies have been performed to induce tolerance using different strategies,
Cellular therapies which included the use of various immunosuppressive drugs targeting B and T lymphocytes in favor of depletion, inhibition of co-stimulation pathways, or upregulation and proliferation of regulatory T cells.
Other than immunosuppressive drugs, tolerance inducing strategies included total lymphoid tissue irradiation and splenectomy.
clinical application for lymphoid tissue was limited because of adverse events, while splenectomy was used in some countries but controversies exist for its application because of is believed that spleen has role in the induction and maintenance of T regulatory cells.
Many recent protocols that aim to induce tolerance in kidney transplantation to avoid the deleterious side effects of immunosuppressive therapies include protocols achieving full donor chimerism or transient mixed chimerism. protocols use donor stem cell and recipient immune system co-exist with one another to achieve the tolerance.
Achieving tolerance to transplanted organ has been an important subject of research
Tolerance is defined as ability of foreign tissue or organ to survive in a host , without immunosuppressive drugs , for at least 1 year in immunocompetent individual capable of responding to other stimuli as infections
The idea of transplant tolerance came from the self tolerance phenomenon, in which autoreactive ,harmful B and T cells ( during the process of maturation ) are been discarded ,in order to avoid any harmful immunresponses
Self tolerance is divided in central tolerance ( in thymus gland and bone marrow ) and peripheral tolerance ( in peripheral blood )
Tolerance to transplant was 1st introduced through experimental animal models in 1950 , and was found to happen spontaneously in some of non adherent patients .
Since then studies have been directed to detection of biomarkers for identification patients who may acquire tolerance .
Biomarkers identifying studies have been evolving over years , finally in 2010, lechler and his colleagues performed multicenter study and concluded that tolerant people have the following
Expanded B cells and NK cells
Fewer activated CD4 cells
Expansion of B cell related genes
No DSAs
Donor specific CD4 hyporesponsivness
Increased expression of Foxp3 gene .
Another point, is the discovery of a process called chimerisim in which small amount of donor cells found in recepient blood capable of inducing tolerance ,
This lead the researchers conclude that , interchange of red cell and leukocyte precursors from donor to recipients ,could lead to tolerance between grafts ( a phenomenon discovered from twin cattles that share red cell precursors of its own and its twin at same time without induced immune reponse ) .
Differed tolerogenic strategies have been proposed including :
Cellular theory
Total lymphoid ablation
Splenectomy
Different protocols applying cellular therapies are now promising , including those causing full donor chimerism , transient / permanent mixed chimerism .
Immune Tolerance is the optimum goal we have to reach in order to obtain better graft and patient survival in absence of immunosuppression medications, hence decreased patient morbidity and mortality related to heavy burden of immunosuppressive drugs (ISD).
Definition of tolerance is the ability of the foreign organ to survive in the host without ISD.
Clinical operational tolerance defined as excellent graft function in absence of histological signs of rejection for 1 year in the host and has the ability to respond to surrounding conditions like infections.
Immunological tolerance is the state of acceptance of the graft inside the host or body who exerts no immunological reaction or response to it in absence of ISDs.
Self-tolerance is the ability of Tcells and B cells to learn how to differentiate between self and non self antigens. It is central and peripheral
Central tolerance defined as a process in which auto reactive T and B cells are eliminated; this happened by deletion ( if immature cells are strong self reactive will be deleted).
T cell in thymus are immature if lack T cell receptor TCR and lack CD4 and CD8 antigens called double negative T cell. But if incorporated with the receptor TCR and when upregulation of CD4 and CD8….these cells become mature…usually immature cells die in thymus before reaching periphery, also immature B cells should not react with its receptors and not inducing immune reaction.
Peripheral tolerance any T and B cell escaped from central tolerance will be destroyed in the periphery.
T reg cells are the main cells responsible for immune tolerance , there is thymus derived T reg regulate central tolerance and peripheral derived T reg controls peripheral tolerance, and also there is in vitro induced Treg.
Tolerance signatures are biomarkers indicate tolerance like hyporesponsiveness donor cells , increase Treg cells and decrease activated T cells, no donor specific antibodies.
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells. As transplantation between monozygotic identical twin.
Microchimerism presence of donor cells in percent less than 1% from all recipient cells circulating in the patient blood as transplantation between dizygotic twins.
Strategies help tolerance induction:
1- Total irradiation of all lymphoid tissues and organs, this is dangerous and inapplicable.
2- Splenectomy…its limitation is present because its role in induction and maintenance of Treg cells.
There are several tolerogenic protocols include T cell depletion, B cell depletion and co stimulation block.
In addition, there are some strategies still under research and development like T and B reg infusion, mixed chimerism…etc.
Excellent start.
Try to use your own words.
Are you aware of any examples of tolerance induction? If yes, please share it with all colleagues.
transforming growth factor beta TGF-β has an important role to keep suppressive effects of Treg cells which are the key of immune tolerance , it suppress differentiation of original cells
also natural killer cells are mediated by TGF-β and has their role against graft versus host disease , so its presence has a role in immune tolerance
M. Sykes. Immune tolerance: mechanisms and application in clinical transplantation. Journal of Internal Medicine. September 2007. Volume 262, Issue3, Pages 288-310.
Over the past few decades, a lot of studies have been performed to induce tolerance using different strategies.
-Cellular therapies which included the use of various immunosuppressive drugs targeting B and T lymphocytes in favor of depletion, inhibition of co-stimulation pathways, or upregulation and proliferation of regulatory T cells. Examples: ATG, Alemtezumab, Betalacept, Efalezumab,Basiliximab, Rituximab, Bortezumab, Eculizumab etc.
-Other than immunosuppressive drugs, tolerance inducing strategies included total lymphoid tissue irradiation and splenectomy. In clinical practice, lymphatic system irradiation is reserved to patients with hematologic malignancies and concomitent end stage renal diseases , in particular multiple myeloma, where total lymphoid irradiation is followed by bone marrow and kidney transplantation.
Any replies?
Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up
Xuanchuan Wang
Methods
From 2009 to 2017
11 donor/recipient pairs underwent living-related kidney transplantation combined with DHSC infusion.
Two of the pairs were human leukocyte antigen (HLA)-matched
nine were HLA-mismatched.
DHSCs were mobilized using granulocyte colony-stimulating factor (G-CSF) and harvested 1 day before transplantation.
The recipients received consecutive total lymphoid irradiation (TLI) for 3 days before kidney transplantation.
The induction drug was anti-thymocyte globulin (ATG).
DHSCs were infused on days 2, 4, and 6 post surgery.
All patients were followed-up until Dec 2019.
Results
Five patients were able to reduce the dose of their immunosuppressive therapy.
mild rejection with Banff grade IA in one patient, while the other ten recipients did not develop rejection.
No increased risk of infections.
One recipient lost allograft function, and 10 recipients had stable renal function.
None developed myelosuppression or GVHD post transplantation.
What are your thoughts about bone marrow and kidney transplantation for patients with multiple myeloma? Do you think this is a tolerogenic strategy? Have you ever heard about such trials?
Specific tolerance has been acheived after combined kidney and bone marrow transplant in multiple myeloma patient as evidenced by prolonged normal renal function without ongoing immunosuppression.
trial
Long-Term Follow-Up of Recipients of Combined Human Leukocyte Antigen-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With End-Stage Renal Disease
Thomas R. Spitzer et al
conclusion- sustained renal allograft tolerance and prolonged antimyeloma responses are achievable after combined kidney and bone marrow Hla matched transplant .
Tolerance in renal transplantation means no immunosuppression is needed in a recipient to avoid rejection of allograft for a sustained period of time.
Donor hematopoietic stem cell transplantation has been used successfully to induce tolerance in clinical kidney transplantation from living donors.
SUMMARY
Tolerance can be-
Clinical operational tolerance-graft like histological signs of rejection without immunosuppression.
Immunological tolerance- no immune reaction against the graft without immunosuppression.
Self tolerance comprises of –
A) Central tolerance-
B cells mature in bone marrow,Tcells mature in Thymus.
when T cells reach thymus they are double negative. their they receive TCR and upregulation of CD4 and CD8 takes place(double positive).in thymic stroma via negative selection self reacting T cells are killed and Via clonal selection non reacting T cells to self are selected and they mature.
Similarly, B cells are also tested for reactivity to self-antigens before they enter the periphery.
B) Peripheral tolerance
By deletion,apoptosis,anergy,regulation or suppression self reaction T and B cells which somehow managed to escape central tolerance are killed.
Main mediator cells of tolerance
Thymus-derived regulatory T (tTreg) cells for central tolerance.
peripherally derived regulatory T (pTreg) cells for peripheral tolerance.
Types of Tolerance signatures or biomarkers
New gene expression signature
Composite score based on 6 genes and 2 demographic parameters.
Characteristics of tolerant patients
expansion of peripheral blood B and NK lymphocytes
fewer activated CD4+ T cells
lack of donor specific antibodies
donor specific hyporesponsiveness of CD4+ T cells
high ratio of FoxP3 to α-1,2 mannosidase gene
expression
differential expression of B cell related genes and
associated molecular pathway.
Chimerism
Chimerism is co-existence of donor and host haematopoietic stem cells inside the host without inducing an immunological reaction against donor cells.Microchimerism can occur from pregnancy ,blood transfusion and previous transplants.
Tolerogenic strategies
T cell
T cell depletion by using ATG or Alemtuzumab
Costimulation blockade by using Abatacept,Belatacept or Efalizumab.
Others- Basiliximab and Alesleukin plus rapamycin
B cell
Rituximab,Belimumab,Ataicicept,Bortezomib,Eculizumab can be used
Mixed chimerism
Using infusion of donor bonr marrow into myeloablated/immune-conditioned receipient .
Infusion of expanded regulatory T cells.
Tolerance:
In spite having foreign well functioning organ inside a host without the use of immunosuppression , no immune reaction .
Self-tolerance:
It is meaning that during maturation ,T and B cells learn to differentiate between self-antigens and non-self (foreign) antigens preventing them to attack self tissue .
It includes central and peripheral tolerance:
*Central tolerance :
Clonal deletion of the potentially auto-reactive T and B cells .
double negative cell:immature cell which lack both the TCR and the antigen CD4 and CD8
double positive cell: incorporation of TCR with upregulation of the CD4 and CD8 .
negative selection : T-cell are eliminated by apoptosis If they strongly react with react with the peptides in thymic stroma (self-peripheral proteins).
Positive selection: T-cells that interact positively to self-protein and become mature T cells
single positive T cells : mature T cells express either CD4 or CD8 receptors represent 3-5% of the original T cells.
T-cell with very low reaction fail to induce survival signals and die within the thymus.
this process is called clonal selection.
Also the B-cells are tested also for reactivity to self-antigen before they are released to the periphery.
The central immune tolerance is the function of thymus-derived regulatory T-cell (t T reg ).
*Peripheral Tolerance :
is killing the self-reactive T and B cells that escape the central tolerance mechanism and enter the peripheral circulation by either the deletion and apoptosis, energy, and regulation or suppression mediated by Peripheral regulatory T cells (pTreg).
Another classification to Treg cell depend on what they express:
A- Classical CD4+ Foxp3+ Treg cells
B- CD4+Foxp3-type 1 regulatory t cell (Tr1)
These expressers become area of researches with promising hope to prevent transplant rejection.
Tolerance signatures: (biomarkers)
Researchers show more interest in identification of the biomarkers of tolerance, as by validation of these biomarkers, there will chance to predict those recipients that will get tolerance with no immunosuppression or minimal dose.
Tolerant patients showed the following characteristics
• expansion of peripheral blood B and NK lymphocytes
• fewer activated CD4+ T cells
• lack of DSA
• donor specific hyporesponsiveness of CD4+ T cells
• high ratio of FoxP3 to α-1,2 mannosidase gene expression
• differential expression of B cell related genes and associated molecular pathways
Chimerism:
It is presence of the donor and host haematopoietic stem cells within the host without causing an immunological reaction against donor cells.
Microchimerism is the presence of donor cells (<1% of all circulating recipient cells) in the recipient body can occur from pregnancy, blood transfusion, and previous transplants.
In liver transplants up to 20% of the recipients develop spontaneous operational tolerance. This can be due to large number of donor leukocytes that come with the transplanted liver and lead to microchimerism in the recipient.
Transplantation between identical monozygotic twins associated with marked tolerance. While, between dizygotic (HLA non-identical) twins, the microchimerism is incomplete and this cause incomplete tolerance.
Tolerogenic strategies
Many protocols have been developed, with an aim to inducing tolerance in kidney transplant recipients. Thereby the immunosuppression can be discontinued.
Cellular therapy to achieve such tolerance are many:
·Total lymphoid elimination protocol includes irradiation of the LN, spleen, and thymus. It has high toxicity. Used in patient with multiple myeloma and co-existing ESRD.
·Splenectomy: splenic irradiation or splenectomy results in elimination of B lymphocytes and Ig M antibodies result in tolerance with immunosuppression. This regime result in graft survival rate exceeding 90% at 5 years.
·Multiple receptor ligand interactions blockade induces transplant tolerance by activation of T cell energy.
·Costimulatory pathways CD 28 receptor that bind to CD80 and CD86 ligands expressed on Ag-presenting cell.
Current tolerogenic strategies in use : in image
Current tolerogenic strategies in use :