1.Transplantation Immunology Dr.T.V.Rao MD

2. Need for TransplantationMany needs in humansDamaged organs,Non Functional organs Dr.T.V.Rao MD 2 3. Nobel Prize in Physiology or Medicine 1912 Alexis Carrel (France) Work on vascular suture and the transplantation of blood vessels and organs2006-7year Great events in history of transplantation Immunology 3 4. Nobel Prize in Physiology or Medicine 1960 Peter Brian Medawar (1/2) Discovery of acquired immunological tolerance The graft reaction is an immunity phenomenon 1950s, induced immunological tolerance to skin allografts in mice by neonatal injection of allogeneic cells2006-7yearGreat events in history of transplantation Immunology4 5. Nobel Prize in Physiology or Medicine 1990 Joseph E. Murray (1/2) Discoveries concerning organ transplantation in the treatment of human disease In 1954, the first successful human kidney transplant was performed between twins in Boston. Transplants were possible in unrelated people if drugs were taken to suppress the bodys immune reaction2006-7yearGreat events in history of transplantationImmunology 5 6. Nobel Prize in Physiology or Medicine 1980George D. Snell (1/3), Jean Dausset (1/3)Discoveries concerning genetically determinedstructures on the cell surface that regulateimmunological reactions H-genes (histocompatibility genes), H-2 gene Human transplantation antigens (HLA) ----MHC2006-7year Great events in history of transplantation Immunology 6 7. Earliest HistorySkin Grafting for Reconstruction ofsevered noseDone with patients own skin ( Sustrutha Samhita )Dr.T.V.Rao MD 7 8. Hindu MythologyA Divine TransplantationDr.T.V.Rao MD8 9. Definition of TransplantationImplantation of non-self tissue into the bodyThe process of taking cells, tissues, or organscalled a graft (transplant), from one part orindividual and placing them into another (usuallydifferent individual).donor : the individual who provides the graft.recipient or host: the individual who receives thegraft. Dr.T.V.Rao MD 9 10. Classification Based on GeneticsGenetic basis is naming different types ofgraftsSelf to Self - Auto graftOne individual to another Isograft(Identical twins) both are genetically similarGrafts between two genetically non identicalmembers of the same species are called asallograft. Dr.T.V.Rao MD 10 11. Other names in TerminologyCan be stored or freshTransplants may be Living or DeadLive grafts Kidney, Hear, also called asVital grafts.Non living Bone, ArteryStatic or structural grafts.Dr.T.V.Rao MD11 12. TypesAutologous graft (autograft) : within an individual,auto transplantationSyngeneic graft (syngraft, isograft) : identical twins,isotransplantationnon-Allogeneic graft (allograft, homograft) : non-identical,allotransplantationXenogeneic graft (heterologous graft, heterograft) :between species, xenotransplantation Dr.T.V.Rao MD12 13. Classification of Transplants Based on nature of organs - Kidney, Liver, Heart, Bone marrow, Skin On basis of Anatomical site Orthotropic, Heterotypic Orthotropic Skin graft Heterotypic graft 0n abnormal site eg Thyroid gland in subcutaneous region Dr.T.V.Rao MD 13 14. Allograft: TransplantTransplant from one individual to another with a different genetic make-up, within the same species, eg. kidneytransplant from one person to any other (except an identical twin).Dr.T.V.Rao MD 14 15. Allograft Dr.T.V.Rao MD 15 16. Isograft or syngeneic graft Transplant betweengenetically identical,monozygotic twins, orbetween members of aninbred strain of animals. Dr.T.V.Rao MD16 17. IsograftDr.T.V.Rao MD 17 18. Autograft:Transplant from one site to another on thesame individual, eg. transplanting a bloodvessel from the leg to the heart during cardiacbypass surgery. This type of transplant doesnot require immunosuppressive therapyEg Skin Grafting in burns, destructive injuries.Dr.T.V.Rao MD18 19. Auto Graft Dr.T.V.Rao MD 19 20. Xenograft:Transplant across species barriers, eg,transplanting a heart from a baboon to ahuman. Have a very poor prognosis becauseof the presence of cross-species reactiveantibodies that will induce hyperacuterejection. Dr.T.V.Rao MD20 21. Other grafts ...When grafted between two differentspecies is called as XENOGRAFTSEg From Pig to HumansAlso called as HeterograftDr.T.V.Rao MD21 22. Xenograft Dr.T.V.Rao MD 22 23. Dr.T.V.Rao MD 23 24. Applications of allografting transplantationDr.T.V.Rao MD24 25. How Grafts are accepted or rejected.AA + BB F1 hybrid AB AB can accept graft from both AA or BB But AA or BB cannot accept the Graft fromABDr.T.V.Rao MD25 26. Dr.T.V.Rao MD 26 27. Classification of Renal TransplantationAuto-Auto-RT CadavericAllograft RT Living related Living DonorLiving unrelatedXenograft RT (In experimental) Dr.T.V.Rao MD27 28. Transplants from Male to FemaleMale tissues contain xyWhen male tissue with xy grafted to female (xx ) as females dont contain y geneThe grafts may not be accepted However grafts done from female to male areaccepted.The Phenomenon is called as unilateral sexlinked Histocompatability is known asEICHWALD SILMSER EFFECT.Dr.T.V.Rao MD28 29. Eichwald Silmser EffectMale to FemaleDr.T.V.Rao MD 29 30. Transplants and the immunesystemDiscrimination between self/nonselfThis is not good for transplantsAt first the only possible transplants wereblood transfusionsOtherwise the grafts were disastrousWhy are blood transfusions tolerated? 31. MAJOR CONCEPTS IN TRANSPLANT IMMUNOLOGYHow does the immune system deal with a transplant, i.e.What are the mechanisms of rejection?What are the current clinical strategies to block rejection?What are the new and future strategies to promote specificimmune tolerance?What is the role of xenotransplantation?What is graft versus host disease? 32. Factors favoring Allograft Survival Blood group compatibilityHLA compatibilityHLA typing and TissuematchingHLA typing identifies the HLAantigens expressed on thesurface of leukocytes. Dr.T.V.Rao MD32 33. Histocompatability Antigens Immune response against transplants depends on the presence in the grafted tissue ofantigens that are absent in recipient and hence recognizedas foreign Dr.T.V.Rao MD 33 34. HLA system Dr.T.V.Rao MD 34 35. Tissue typingMicrocytotoxicity assay Known antibody to WBCs of donor / recipient Complement mediated lysis if Ab present on cell surfaceMixed lymphocyte culture (MLC) Irradiated donor lymphocytes (stimulants) Incubated with recipient lymphocytesFlow cytometry cross typingDNA analysisGenomic typing (very precise, many subtipes) 36. Clinical phases of rejection1. Hyperacute rejection (minutes to hours) Preexisting antibodies to donor HLA antigens Complement activation, macrophages2. Accelerated rejection3. Acute rejection (around 10 days to 30 days) Cellular mechanism (CD4, CD8, NK, Macrophages)4. Chronic rejection (months to years !!) Mixed humoral and cellular mechanism CHRONIC REJECTION IS STILL HARD TO MANAGE ! Dr.T.V.Rao MD36 37. Graft acceptance If the recipient posses allthe antigens present inthe graft, there will beimmune response, andthere will be no immuneresponse, and no graftrejection even when thedonor and recipient arenot syngeneic. Dr.T.V.Rao MD 37 38. Mechanism of acceptance and rejection The first generation Hybridsbetween two inbred strains possesantigens representing both theparent strains and will accept graftsfrom either parent strains andtherefore accept grafts from either ofstrains.the parental strainsDr.T.V.Rao MD 38 39. Peritransplant injury induces chemokines thatincrease inflammation and immunity Devries, 2003, Sem in Imm 15:33-48 40. Control of Transplant ImmunologyTransplantation immunity ispredominately by cell mediatedimmunityFirst response is mediated by TlymphocytesHumoral antibody are also producedduring Allograft Rejection Dr.T.V.Rao MD 40 41. What happens after Two to ThreedaysThe site around transplantation is inflamed,invaded by lymphocytes, MacrophagesBlood vessels occluded by thrombiVascularity to graft diminishesIschemic changes sets inScab like changes appear, sloughs out 10th day Above response is called Ist set responseDr.T.V.Rao MD41 42. Cellular and Molecular Understandings Associated with graft rejections and immunosuppressive therapies Rejection has not been eliminated only reducedHyperacute rejectionAcute rejectionChronic rejection 43. The Allograft RejectionWhat Happens Skin from one animal isaccepted initially Vacularised Appears healthy for shortperiod for two or three daysInflammation sets inDr.T.V.Rao MD43 44. Hyperacute RejectionOccurs within a few minutes to a few hoursResult of destruction of the transplant by performed antibodies (cytoxic antibodies)Some produced by recipient before transplantGenerated because of previous transplants, blood transfusions, and pregnanciesAntibodies activate the complement system then platelet activation and depositioncausing hemorrhaging and swelling 45. When the Graft will be accepted If An allograft will be madeacceptable if animal ismade immunologicallytolerantDr.T.V.Rao MD45 46. Chronic rejectionCaused by both antibody and cell-mediated immunityMay occur months to years down the road in allografttransplants after normal function has been assumedImportant to point out rate, extent, and underlyingmechanisms of rejection that vary depending on tissue andsiteThe recipients circulation, lymphatic drainage, expression ofMHC antigens and other factors determine the rejection rateInflammation, smooth muscle proliferation, fibrosisTissue ischemia 47. Role of MHC moleculesWhen T cells are exposed to foreign cells expressing non-self MHC, many clones are tricked into activation - theirTCRs bind to foreign MHC-peptide complexs presented T cells are reacting directly with the donor APCs expressingallogeneic MHC in combination with peptide. These donorAPCs also have costimulatory activity to generate thesecond signal for the second reaction to occurMinor H antigens are encoded by genes outside the MHC 48. Laboratory TestsABO Blood typingTissue typing (HLA Matching)(Lymphocytotoxicity test)(Mixed leukocyte reaction)Screening for Presence of PreformedAntibodies to allogeneic HLACrossmatching 49. Prolonging Allograft Survival Anti-inflammatory Agents Cytotoxic Drugs Agents that interfere with Cytokine production and signaling Immunosuppressive Therapies New Immunosuppressive strategies 50. Nobel Prize in Physiology or Medicine 1988Gertrude B. Elion (1/3) , George H. Hitchings (1/3)Discoveries of important principles for drugtreatment Immunosuppressant drug (The first cytotoxic drugs) ----- azathioprine2006-7yearGreat events in history of transplantation Immunology 50 51. Prolonging Allograft SurvivalCyclosporine and Tacrolimus (FK-506)AzathioprineMycophenolate MofetilRapamycineCorticosteroidsAnti-CD3, Anti-CD52, Anti-IL-2, AntiCD25 52. Most Important Organ transplantation Dr.T.V.Rao MD 52 53. Graft-vs-Graft-vs-host diseaseGraft-vs-host disease can occur in the specialcase in which immunocompetent tissue (freshwhole blood, thymus, or bone marrow) istransplanted into an immunocompromised host. Tcells from the transplant recognize the host MHCmolecules as nonself and attack the host. This isa type IV hypersensitivity reaction; antibody playsno role at all. Dr.T.V.Rao MD53 54. Privileged SitesFetus survives The placenta acts asimmunologicalbarrier MHC are present inlow density Alpha-Alpha-fetoprotein inblood will help Cornea survivebecause of lack ofvascularity Dr.T.V.Rao MD 54 55. Bone MarrowAttempts to use these cells have been aroundfor at least 60 yearsExplored intensely since world war IIUsed for treating blood diseases, severecombined immunodiffency and leukemiaThis type of transplant is also called a form ofgene therapy 56. Source of stem cells for TransplantsPeripheral Blood Stem Cells (PBSCT)Stem cells collected peripherally using apheresis (cellseparator machine) Less invasive; less discomfort; less morbidity than BMOutpatient procedurePBSCT results in more rapid hematopoietic recovery thanBMNo difference in treatment outcomeQuickly replacing traditional BM Using cytokine stimulation (G-CSF injections) BM releases large number CD34 stem cells into circulation Stem cells harvested via peripheral line 57. Graft Host reactionGraft rejection is due to the reaction ofthe host to grafted tissue ( host versus-graft response ) In contrary Graft mounts an immuneresponse against the antigens of thehost ( GVH )Dr.T.V.Rao MD 57 58. GVH reaction occurs when1 The graft contains immunocompetent T cells 2 The recipient possesses transplantation antigens that are absent in the graftThe recipient must not reject thegraft Dr.T.V.Rao MD 58 59. Situation leading for GVHAllograft in a recipient in whom specific immunologicaltolerance has been induced Present with clinically Retardation of growth Diarrhea, Hepatosplenomegaly Lymphoid atrophy Anemia Terminating fatallySyndrome is called Runt disease Dr.T.V.Rao MD59 60. Created by Dr.T.V.Rao MD for benefit of Undergraduate Students in Immunologyand Microbiology in Developing worldEmail doctortvrao@gmail.com