immunology15 immunology

1、TransplantationImmunology1Outlinesn Introductionn Immunologic Basis of Allograft Rejectionn Classification and Effecter Mechanisms of allograft rejectionn Prevention and Treatment of Allograft Rejectionn Xenotransplantation2Introduction34Nobel Prize in Physiology or Medicine 1912n Alexis Carreln Wor

2、k on vascular sutureand the transplantation of blood vessels and organsGreat events in history of transplantation5Nobel Prize in Physiology or Medicine 1960n Peter Brian Medawarn Discovery of acquiredimmunological tolerancen The graft reaction is an immunity phenomenonn 1950s, induced immunological

3、tolerance to skin allografts in mice by neonatal injection of allogeneic cellsGreat events in history of transplantation1.自体/同系移植不排斥，同种异体移植排斥；2.首次排斥（术后10-13天），再次排斥（6-8天）；3. 再次移植无关个体皮肤，则排斥时间为10-13天；4. 移植到裸鼠，排斥（-）；输入无关个体T细胞，则 排斥（+）；5. 发现免疫耐受6证据：小鼠皮肤移植实验7Nobel Prize in Physiology or Medicine 1980n Geor

4、ge D. Snell, Jean Daussetn Discoveries concerning genetically determined structures on the cell surfacethat regulate immunological reactionsn H-genes (histocompatibility genes), H-2 genen Human transplantation antigens (HLA)MHCGreat events in history of transplantation8Nobel Prize in Physiology or M

5、edicine 1988n Gertrude B. Elion, George H. Hitchingsn Discoveries of important principles for drug treatmentn Immunosuppressant drug (The first cytotoxic drugs) - azathioprine (硫唑嘌呤)Great events in history of transplantation9Nobel Prize in Physiology or Medicine 1990n Joseph E. Murrayn Discoveries c

6、oncerning organ transplantation in thetreatment of human diseasen In 1954, the first successful human kidney transplant was performed between twins in Boston.n Transplants were possible in unrelated people if drugs were taken to suppress the bodys immune reactionGreat events in history of transplant

7、ationToday, kidney, pancreas, heart, lung, liver, bone marrow, and cornea transplantations are performedamong non-identical individuals with ever increasing frequency and success.10Conceptsn Transplantationn Graftsn Donorsn Recipients or hostsn Orthotopic transplantationn Transplantation of a donor

8、organ graft into the same site as that occupied by the original organ that failedn Heterotopic transplantationn transplantation of a tissue to a place it is not normally found11Classification of graftsn Autologous grafts (Autografts)n Grafts transplanted from one part of the body to another in the s

9、ame individualn Syngeneic grafts (Isografts)n Grafts transplanted between two genetically identical individuals of the same speciesn Allogeneic grafts (Allografts)n Grafts transplanted between two genetically different individuals of the same speciesn Xenogeneic grafts (Xenografts)n Grafts transplan

10、ted between individuals of different species1213Genetic basis of transplant rejectionInbred mouse strains - all genes are identicalTransplantation of skin between strains showed that rejection or acceptance was dependent uponthe genetics of each strainACCEPTEDSkin from an inbred mouse grafted onto t

11、he same strain of mouseREJECTEDSkin from an inbred mouse grafted onto a different strain of mouse14Immunological basis of graft rejectionPrimary rejection ofstrain skine.g. 10 daysTransfer lymphocytes from primed mouse6 monthsLycSecondary rejection ofstrain skine.g. 3 daysNave mousePrimary rejection

12、 ofstrain skinTransplant rejection is due to an antigen- specific immune response with immunological memorye.g. 10 days15n Grafts rejection is a kind of specific immune responsen Specificityn Immune memory1617Immunologic Basis ofAllograft Rejection18I. Transplantation antigensn Major histocompatibil

13、ity antigens (MHC molecules)n Minor histocompatibility antigensn Other alloantigens191. Major histocompatibility antigensn Main antigens of grafts rejectionn Cause fast and strong rejectionn Difference of HLA types is the main cause of human grafts rejection202. Minor histocompatibility antigensn Al

14、so cause grafts rejection, but slow and weakn Mouse H-Y antigens encoded by Ychromosomen HA-1HA-5 linked with non-Y chromosome21223. Other alloantigensn Human ABOblood group antigensn Some tissue specific antigensn Skinkidneyheartpancreas livern VEC antigen23II. Mechanism of allograft rejectionn Cel

15、l-mediated Immunityn Humoral Immunityn Role of NK cells241. Cell-mediated Immunityn Recipients T cell-mediated cellular immune response against alloantigens on grafts25Molecular Mechanisms of Allogeneic Recognitionn Many T cells can recognize allogenetic MHC moleculesn 1%-10% of T cells recognize al

16、logeneticMHC moleculesn T cells of the recipient recognize the allogenetic MHC moleculesn Direct Recognitionn Indirect Recognition26Direct Recognitionn Recognition of an intact allogenetic MHC molecule displayed by donor APC in the graftn Cross recognitionn An allogenetic MHC molecule with a bound p

17、eptide can mimic the determinant formed by a self MHC molecule plus foreign peptiden A cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus foreign peptide, with an allogenetic MHC molecule plus peptide27n Cross recognition28n Passenger leukocytesn Donor APCs tha

18、t exist in grafts, such as DC, Mn Early phase of acute rejectionn Fast and strong29Indirect recognitionUptake and presentation of allogeneic donor MHC molecules by recipient APC in “normal way”Recognitionby T cells like conventionalforeign antigensSlow and weakLate phase of acute rejection and chron

19、ic rejectionCoordinated function with direct recognition in early phase of acute rejection3031Difference between Direct Recognition and Indirect RecognitionDirect RecognitionIndirect RecognitionAllogeneic MHC moleculeIntact allogeneic MHC moleculePeptide of allogeneic MHC moleculeAPCsRecipient APCs

20、are not necessaryRecipient APCsActivated T cellsCD4T cells and/or CD8T cellsCD4T cells and/or CD8T cellsRoles in rejectionAcuterejectionChronic rejectionDegree of rejectionVigorousWeak32Role of CD4T cells and CD8T cellsn Activated CD4+T by direct and indirect recognitionn CK secretionn M activation

21、and recruitmentn Activated CD8+T by direct recognitionn Kill the graft cells directlyn Activated CD8+T by indirect recognitionn Can not kill the graft cells directly332. Humoral immunityn Important role in hyperacute rejection(Preformedantibodies)n Complements activationn ADCCn Opsonization343 .Role

22、 of NK cellsn KIR cant recognize allogeneic MHC ongraftn CKs secreted by activated Th cells canpromote NK activation35Mechanisms of graft rejectionTNFa, NO2IL2, TNFb, IFN gInflammationIL2, IL4, IL5lysisIL2, IFN gADCClysisRejection36Classification and EffecterMechanisms of AllograftRejection37Classif

23、ication of Allograft Rejectionn Host versus graft reaction (HVGR)n Conventional organ transplantationn Graft versus host reaction (GVHR)n Bone marrow transplantationn Immune cells transplantation38I. Host versus graft reaction (HVGR)n Hyperacute rejectionn Acute rejectionn Chronic rejection391. Hype

24、racute rejectionn Occurrence timen Occurswithin minutes to hours after hostblood vessels are anastomosed to graftvesselsn Pathologyn Thrombotic occlusion of the graft vasculaturen Ischemia, denaturation, necrosis40n Mechanismsn Preformed antibodiesn Antibody against ABO blood type antigenn Antibody

25、against VEC antigenn Antibody against HLA antigenn Complement activationn Endothelial cell damagen Platelets activationn Thrombosis, vascular occlusion, ischemic damage4142n Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infilt

26、ration in a glomerulus432. Acute rejectionn Occurrence timen Occurs within days to2 weeks aftertransplantation, 80-90% of cases occur within 1 monthn Pathologyn Acute humoralrejectionn Acute vasculitis manifested mainly by endothelial cell damagen Acute cellular rejectionn Parenchymal cell necrosis

27、along with infiltration of lymphocytes and M44n Mechanismsn Vasculitisn IgG antibodies against alloantigens onendothelial celln Parenchymal cell damagen Delayed hypersensitivity mediated by CD4+Th1n Killing of graft cells by CD8+Tc4546Acute rejection of a kidney with inflammatory cells in the inters

28、titium and between epithelial cells of the tubules473. Chronic rejectionn Occurrence timen Develops months or years after acute rejection reactions have subsidedn Pathologyn Fibrosis and vascular abnormalities with loss of graft function48n Mechanismsn Not clearn Extension and results of cell necros

29、is inacute rejectionn Chronic inflammation mediated by CD4+T cell/Mn Organ degeneration induced by non immune factors4950Kidney Transplantation-Graft Rejection51II. Graft versus host reaction (GVHR)n Graft versus host reaction (GVHR)n Allogenetic bone marrow transplantationn Rejection to host alloan

30、tigensn Mediated by immune competent cells in bone marrown Graft versus host disease (GVHD)n A disease caused by GVHR, which can damage the host52n Graft versus host disease53n Graft versus host disease54Conditionsn Enough immune competent cells in graftsn Immunocompromised hostn Histocompatability

31、differences between host and graft55n Bone marrow transplantationn Thymus transplantationn Spleen transplantationn Blood transfusion of neonateIn most cases the reaction is directed against minor histocompatibility antigens of the host561. Acute GVHDn Endothelial cell death in the skin, liver, and g

32、astrointestinal tractn Rash, jaundice, diarrhea,gastrointestinal hemorrhagen Mediated by mature T cells in the grafts57n Acute graft-versus-host reaction with vivid palmar erythema582. Chronic GVHDn Fibrosis and atrophy of one or more of the organsn Eventually complete dysfunction of theaffected org

33、an59n Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on kneen Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back60Both acute and chronic GVHD are commonly treated with intense immunosuppresion.61Prevention andTherapy of AllograftRejection62n Tissue Typingn Immunosuppressive Therapyn Induction of Immune Tolerance63I. Tissue Typingn ABO and Rh b