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IMMUNOLOGY OF IMMUNOLOGY OF TRANSPLANTATIONTRANSPLANTATION
Prof.Mohammed Al-homranyProf.Mohammed Al-homrany
MAJOR CONCEPTS IN MAJOR CONCEPTS IN TRANSPLANT IMMUNOLOGYTRANSPLANT IMMUNOLOGY
How does the immune system deal with a How does the immune system deal with a transplant, i.e. What are the mechanisms of transplant, i.e. What are the mechanisms of rejection?rejection?
What are the current clinical strategies to block What are the current clinical strategies to block rejection?rejection?
What are the new and future strategies to promote What are the new and future strategies to promote specific immune tolerance?specific immune tolerance?
What is the role of xenotransplantation?What is the role of xenotransplantation?
What is graft versus host disease?What is graft versus host disease?
Basics of ImmunosuppressionBasics of Immunosuppression
Immune system distinguishes self from non-selfImmune system distinguishes self from non-self
Antigen: anything that can trigger an immune Antigen: anything that can trigger an immune responseresponse
B-cell (lymphocyte) – secretes antibodies, B-cell (lymphocyte) – secretes antibodies, presents antigen to T-cellpresents antigen to T-cell
T-cell (lymphocyte), secretes cytokines (ex. IL-T-cell (lymphocyte), secretes cytokines (ex. IL-2), directs and regulates immune responses, 2), directs and regulates immune responses, also attacks infected, cancerous or foreign cellsalso attacks infected, cancerous or foreign cells
Basics of ImmunosuppressionBasics of Immunosuppression
Immune system distinguishes self from non-selfImmune system distinguishes self from non-self
Antigen: anything that can trigger an immune Antigen: anything that can trigger an immune responseresponse
B-cell (lymphocyte) – secretes antibodies, B-cell (lymphocyte) – secretes antibodies, presents antigen to T-cellpresents antigen to T-cell
T-cell (lymphocyte), secretes cytokines (ex. IL-T-cell (lymphocyte), secretes cytokines (ex. IL-2), directs and regulates immune responses, 2), directs and regulates immune responses, also attacks infected, cancerous or foreign cellsalso attacks infected, cancerous or foreign cells
Basics of ImmunosuppressionBasics of Immunosuppression
Cytokines are chemical messengers – bind to Cytokines are chemical messengers – bind to target cells, encourage cell growth, trigger cell target cells, encourage cell growth, trigger cell activity, direct cell traffic, destroy target cells, activity, direct cell traffic, destroy target cells, and activate phagocytes (“cell eaters”)and activate phagocytes (“cell eaters”)
IL-2 activates T-cells and causes proliferation IL-2 activates T-cells and causes proliferation
T-cell surface markers (CD3, CD25, CD52 and T-cell surface markers (CD3, CD25, CD52 and T-cell receptor) CD=cluster of differentiation of T-cell receptor) CD=cluster of differentiation of T-cellsT-cells
MAJOR HISTOCOMPATIBILITY COMPLEX MAJOR HISTOCOMPATIBILITY COMPLEX (MHC(MHC))
Is located on short arm of chromosome 6Is located on short arm of chromosome 6 It includes 3 regionsIt includes 3 regions: class Ia: class Ia (loci A, B, C) (loci A, B, C)
class Ibclass Ib (loci E, F, G, H), (loci E, F, G, H), class IIclass II (loci DR, DQ, (loci DR, DQ, DP) and DP) and class IIIclass III
Genes of class Ia and class II are highly Genes of class Ia and class II are highly polymorphic, while those of class Ib and class polymorphic, while those of class Ib and class III are notIII are not
Polymorphism means occurence of several Polymorphism means occurence of several allelles ie.genes allelles ie.genes enencoding various MHC coding various MHC antigens located at the same locusantigens located at the same locus
MAJOR HISTOCOMPATIBILITY ANTIGENSMAJOR HISTOCOMPATIBILITY ANTIGENS
Histocompatibility antigens are cell surface Histocompatibility antigens are cell surface
expressed on all cells (class I) and on APC, expressed on all cells (class I) and on APC,
B cells, monocytes/macrophages (class II)B cells, monocytes/macrophages (class II)
They are targets for rejectionThey are targets for rejection
They are inherited from both parents as MHC They are inherited from both parents as MHC
haplotypes and are co-dominantly expressedhaplotypes and are co-dominantly expressed
MINOR HISTOCOMPATIBILITY ANTIGENSMINOR HISTOCOMPATIBILITY ANTIGENS
They also participate in rejection but to lesser They also participate in rejection but to lesser degreedegree
Disparity of several minor antigens may result Disparity of several minor antigens may result in rejection, even when MHC antigens are in rejection, even when MHC antigens are concordant between donor and recipientconcordant between donor and recipient
They include blood group antigens, tissue They include blood group antigens, tissue and organ antigens, normal cellular and organ antigens, normal cellular constituentsconstituents
They are peptides derived from polymorphic They are peptides derived from polymorphic cellular proteins bound to MHC class I moleculescellular proteins bound to MHC class I molecules
What is Tolerance?What is Tolerance?
Immunologic unresponsiveness by the Immunologic unresponsiveness by the recipient to the graft in the absence of recipient to the graft in the absence of maintenance immunosuppression.maintenance immunosuppression.
Self-nonself discriminationSelf-nonself discrimination
Self
No response Strong response
Non-selfor foreign
ToleranceTolerance
Tolerance--->specific Tolerance--->specific unresponsiveness triggered by unresponsiveness triggered by previous exposure to Ag.previous exposure to Ag.
Natural Tolerance (self tolerance)Natural Tolerance (self tolerance): : Unresponsiveness to self Ags.Unresponsiveness to self Ags.
Acquired toleranceAcquired tolerance::
Unresponsiveness to foreign Ags.Unresponsiveness to foreign Ags.
ToleranceToleranceToleranceTolerance
Why is it important to study tolerance?Why is it important to study tolerance?
AutoimmunityAutoimmunityCancerCancerTransplantationTransplantation InfectionsInfectionsVaccinesVaccines
TYPES OF GRAFTSTYPES OF GRAFTS
Autologous graft (autograft)Autologous graft (autograft) – in the same – in the same individual: from one site to another oneindividual: from one site to another one
Isogenic (isograft)Isogenic (isograft) – between genetically – between genetically identical individualsidentical individuals
Allogeneic (allograft or homograftAllogeneic (allograft or homograft)) – between – between different members of the same speciesdifferent members of the same species
Xenogeneic (xenograft)Xenogeneic (xenograft) – between mmbers of – between mmbers of different speciesdifferent species
MECHANISMS OF MECHANISMS OF REJECTIONREJECTION
MECHANISMS OF REJECTIONMECHANISMS OF REJECTION
Depend on disparity of genetic background Depend on disparity of genetic background between donor and recipientbetween donor and recipientT cells are critical in graft rejectionT cells are critical in graft rejectionRejection responses in molecular terms, are due Rejection responses in molecular terms, are due to TCR-MHC interactionto TCR-MHC interactionGraft and host MHC molecules present different Graft and host MHC molecules present different peptidespeptidesDifferent MHC molecules have different peptide-Different MHC molecules have different peptide-binding groovesbinding groovesT lymphocytes can directly recognize and T lymphocytes can directly recognize and respond to foreign MHC moleculesrespond to foreign MHC molecules
ALLOREACTIVE CELLS ARE SO ALLOREACTIVE CELLS ARE SO COMMON, BECAUSE:COMMON, BECAUSE:
Foreign MHC molecules differ from self MHC at Foreign MHC molecules differ from self MHC at
multiple different aminoacid residues, each of multiple different aminoacid residues, each of
which may produce determinant recognized by which may produce determinant recognized by
a different cross-reactive T cell clonea different cross-reactive T cell clone
Thus, each foreign MHC molecule is recognized Thus, each foreign MHC molecule is recognized
by multiple clones of T cellsby multiple clones of T cells
2% of host T cells are capable recognizing and 2% of host T cells are capable recognizing and
responding to a single MHC foreign moleculeresponding to a single MHC foreign molecule
Types OF REJECTIONTypes OF REJECTION
Hyperacute rejectionHyperacute rejection antibodies to HLA and ABO blood group system antibodies to HLA and ABO blood group system (hours or first days)(hours or first days)
Acute rejectionAcute rejection T cells (days or weeks)T cells (days or weeks)
Chronic rejectionChronic rejection various mechanisms: cell-mediated, deposition various mechanisms: cell-mediated, deposition of antibodies or antigen antibody complexes with of antibodies or antigen antibody complexes with subsequent obliteration of blood vessels and subsequent obliteration of blood vessels and interstitial fibrosis (months or years)interstitial fibrosis (months or years)
PATHOGENESIS OF CHRONIC REJECTIONPATHOGENESIS OF CHRONIC REJECTION
Is the result of organ damage by Is the result of organ damage by immunologic and non-immunologic factorsimmunologic and non-immunologic factors
Initially – the minor damage and activation Initially – the minor damage and activation of endothelium by cytotoxic T cells and of endothelium by cytotoxic T cells and antibodiesantibodies
PATHOGENESIS OF CHRONIC REJECTIONPATHOGENESIS OF CHRONIC REJECTION -2 -2
Production by endothelial cells biologically active Production by endothelial cells biologically active mediators (PDGF, PAF, TNF, thromboxans etc.)mediators (PDGF, PAF, TNF, thromboxans etc.)
Secretion of cytokines by infiltrating lymphocytesSecretion of cytokines by infiltrating lymphocytes
Mitogenic effect on myocytes and fibroblasts Mitogenic effect on myocytes and fibroblasts results in cell proliferation and fibrosisresults in cell proliferation and fibrosis
Histology of graft rejectionHistology of graft rejection
VARIABLES DETERMINING TRANSPLANT OUTCOMEVARIABLES DETERMINING TRANSPLANT OUTCOME
Donor-host antigenic disparityDonor-host antigenic disparity
Strength of host anti donor responseStrength of host anti donor response
Immunosuppressive regimenImmunosuppressive regimen
The condition of the allograftThe condition of the allograft
Primary disease of the hostPrimary disease of the host
CHRONIC REJECTION IS MORE FREQUENT WHEN:CHRONIC REJECTION IS MORE FREQUENT WHEN:
Were previous epiWere previous epissodes of acute rejectionodes of acute rejection
There is a low number of compatible HLA There is a low number of compatible HLA antigens with recipientantigens with recipient
PatientPatient on on inadequate immunosuppression inadequate immunosuppression
CHRONIC REJECTION IS MORE FREQUENT WHEN:CHRONIC REJECTION IS MORE FREQUENT WHEN:
In the case of cytomegaly virus infectionIn the case of cytomegaly virus infection
The period of organ storage was too longThe period of organ storage was too long
Patient is heavy smoker and/or is Patient is heavy smoker and/or is
hyperlipidemichyperlipidemic
Organ mass is unproportionally small as Organ mass is unproportionally small as
compared to body masscompared to body mass
Immunosuppressive Immunosuppressive AgentsAgents
Management of a Transplant RecipientManagement of a Transplant Recipient
Induction TherapyInduction Therapy: administer medications that : administer medications that provide marked suppression prior to and during provide marked suppression prior to and during the first week post transplantation, some agents the first week post transplantation, some agents can also block B-cell mediated rejectioncan also block B-cell mediated rejection
Maintenance TherapyMaintenance Therapy: administer : administer immunosuppressive agents continuously to immunosuppressive agents continuously to prevent acute rejectionprevent acute rejection
Administer medications to induce Tolerance?Administer medications to induce Tolerance?
History of Kidney TransplantationHistory of Kidney Transplantation
1950’s1950’sFirst successful kidney transplant First successful kidney transplant Total body irradiation for immunosuppressionTotal body irradiation for immunosuppressionSteroidsSteroids
1960’s1960’sAzathioprineAzathioprine
1970’s1970’sPolyclonal anitbodies – anti-lymphocyte globulin (now Polyclonal anitbodies – anti-lymphocyte globulin (now AtgamAtgam, Thymoglobulin, Thymoglobulin))
1980’s1980’sCyclosporine (Sandimmune Cyclosporine (Sandimmune ), “triple drug therapy”), “triple drug therapy”Monoclonal antibody, OKT3 (Orthoclone Monoclonal antibody, OKT3 (Orthoclone ) in 1985) in 1985
IImmunosuppressant Discoveries 1990-2000mmunosuppressant Discoveries 1990-2000
Tacrolimus (PrografTacrolimus (Prograf))
Mycophenolate Mofetil (Cellcept Mycophenolate Mofetil (Cellcept ) )
Basiliximab (Simulect Basiliximab (Simulect ) )
Cyclosporine Microemulsion (Neoral Cyclosporine Microemulsion (Neoral ))
Daclizumab (Zenapax Daclizumab (Zenapax ))
Rabbit Antithymocyte globulin (Thymoglobulin Rabbit Antithymocyte globulin (Thymoglobulin ))Sirolimus (Rapamune Sirolimus (Rapamune ))
MODERN IMMUNOSUPPRESSIVE THERAPYMODERN IMMUNOSUPPRESSIVE THERAPY
CCyyclosporinclosporin (CsA), (CsA), TacrolimusTacrolimus (FK-506) – inhibit IL-2 (FK-506) – inhibit IL-2 production by T cellsproduction by T cells calcineurin antagonistcalcineurin antagonist
Sirolimus (rapamycinSirolimus (rapamycin) – inhibits ) – inhibits signals transmitted by signals transmitted by IL-2 binding to IL-2RIL-2 binding to IL-2R (antiproliferating effect) (antiproliferating effect)
AzathioprineAzathioprine – reduces numbers and function both, T – reduces numbers and function both, T and B cells, by inhibition of purine metabolismand B cells, by inhibition of purine metabolism
MODERN IMMUNOSUPPRESSIVE THERAPYMODERN IMMUNOSUPPRESSIVE THERAPY -2 -2
Mycophenolate mofetilMycophenolate mofetil (MMF) – inhibits DNA (MMF) – inhibits DNA synthesis and protein glycosylationsynthesis and protein glycosylation
Anti-IL-Anti-IL-2 monoclonal antibodies2 monoclonal antibodies
FTY 720FTY 720 – dramatic effect on lymphocyte – dramatic effect on lymphocyte migrationmigration
GRAFT VERSUS HOST GRAFT VERSUS HOST DISEASE (GVHDISEASE (GVH))
GRAFT VERSUS HOST DISEASE (GVHGRAFT VERSUS HOST DISEASE (GVH))
Is common complication in recipients of Is common complication in recipients of bone marrow transplantsbone marrow transplants
Is due to the presence of alloreactive T Is due to the presence of alloreactive T cells in the graftcells in the graft
It results in severe tissue damage, It results in severe tissue damage, particularly to the skin and intestineparticularly to the skin and intestine
GRAFT VERSUS HOST DISEASE (GVH)GRAFT VERSUS HOST DISEASE (GVH)
It may be avoided by careful typing, It may be avoided by careful typing, removal of mature T cells from the graft removal of mature T cells from the graft and by immunosuppressive drugsand by immunosuppressive drugs
It is manifested by marked rise of several It is manifested by marked rise of several cytokines in patient’s serum (IFN-cytokines in patient’s serum (IFN-, TNF, , TNF, IL-1, IL-2, IL-4)IL-1, IL-2, IL-4)
RISK FACTORS IN FORMATION OF GVHRISK FACTORS IN FORMATION OF GVH
Acute GVHAcute GVHPrevious pregnancies in Previous pregnancies in female donorfemale donor
High T cell number in High T cell number in marrowmarrow
HLA disparityHLA disparity
Transplant from female to Transplant from female to malemale
Low immunosuppressionLow immunosuppression
Herpes virus infectionHerpes virus infection
Chronic GVHChronic GVHAging of donor and Aging of donor and recipientrecipient
Donor’s leukocyte Donor’s leukocyte transfusiontransfusion
Previous acute GVHPrevious acute GVH
High dosage radiationHigh dosage radiation
Transplant from female to Transplant from female to manman
HLA disparity HLA disparity
Xenogeneic Xenogeneic transplantationtransplantation
PERSPECTIVES OF XENOGENEIC GRAFTSPERSPECTIVES OF XENOGENEIC GRAFTS
Potential advantage due to larger Potential advantage due to larger accessibility of animal organsaccessibility of animal organs
Monkeys are apparently the most suitable Monkeys are apparently the most suitable donors, but dangerous because of donors, but dangerous because of potential risk of retrovirus transfer within potential risk of retrovirus transfer within graftgraft
PERSPECTIVES OF XENOGENEIC GRAFTSPERSPECTIVES OF XENOGENEIC GRAFTS
Pigs are now considered because of Pigs are now considered because of similar sizes of organs and erythrocytes to similar sizes of organs and erythrocytes to human oneshuman ones
The major obstacle – presence in man The major obstacle – presence in man (1%) of natural antibodies vs.(1%) of natural antibodies vs. Gal Gal (galactose-(galactose--1,3-galactose) causing -1,3-galactose) causing hyperacute rejectionhyperacute rejection
Xenogenic TransplantationXenogenic Transplantation
>50,000 people that need organs die while waiting for a >50,000 people that need organs die while waiting for a donordonor
Studies are underway involving nonhuman organs Studies are underway involving nonhuman organs
Attention has been focused on the pig but the problem is the Attention has been focused on the pig but the problem is the existence of natural or preformed antibodies to carbohydrate existence of natural or preformed antibodies to carbohydrate moieties expressed in the grafts endothelial cellsmoieties expressed in the grafts endothelial cells
As a consequence activation of the compliment cascade As a consequence activation of the compliment cascade occurs rapidly and hyperacute rejection ensuesoccurs rapidly and hyperacute rejection ensues
Concern has given to debate about the safe use of Concern has given to debate about the safe use of xenografts and animal tissues that the tissues might harbor xenografts and animal tissues that the tissues might harbor germsgerms
stem cells for stem cells for TransplantsTransplants
Source of stem cells for Source of stem cells for Transplants Transplants
Bone Marrow graftBone Marrow graft
Peripheral Blood Stem Cells Peripheral Blood Stem Cells (PBSCT)(PBSCT)
Umbilical cordUmbilical cord
Peripheral Blood Stem Cells (PBSCT)Peripheral Blood Stem Cells (PBSCT)Stem cells collected peripherally using apheresis (cell Stem cells collected peripherally using apheresis (cell separator machine)separator machine)
Less invasive; less discomfort; less morbidity than BMLess invasive; less discomfort; less morbidity than BM
Outpatient procedureOutpatient procedurePBSCT results in more rapid hematopoietic recovery PBSCT results in more rapid hematopoietic recovery than BMthan BMNo difference in treatment outcomeNo difference in treatment outcomeQuickly replacing traditional BMQuickly replacing traditional BM
Using cytokine stimulation (G-CSF injections)Using cytokine stimulation (G-CSF injections) BM releases large number CD34 stem cells into circulationBM releases large number CD34 stem cells into circulation Stem cells harvested via peripheral lineStem cells harvested via peripheral line
Source of stem cells for Source of stem cells for Transplants Transplants
Goals of Transplant ResearchGoals of Transplant Research
Prevent rejection and graft lossPrevent rejection and graft loss
Reduce the amount of immunosuppressionReduce the amount of immunosuppression Decrease side effectsDecrease side effects Decrease toxicity and long term effectsDecrease toxicity and long term effects
Enhance long term patient and graft survivalEnhance long term patient and graft survival
Provide reasonable cost effective therapyProvide reasonable cost effective therapy
Improve patient adherence and quality of lifeImprove patient adherence and quality of life
Induce Tolerance (no long term medications, reduces Induce Tolerance (no long term medications, reduces adverse effects, improves quality of life)adverse effects, improves quality of life)