Chapter21 Transplantation Immunology

1. Chapter21 Transplantation Immunology

3. History of transplantation 年代 学者 主要贡献 1900 Landsteiner*(1930) 确定人红细胞主要的同种抗原　 1912 Carrell* 器官移植　 1948 Snell和Gorer 发现小鼠H-2系统及其与组织移植的关系 1953 Snell*(1980) H-2系统由K、D两个位点组成　 1958 Dausset*(1980) 发现第一个人类白细胞抗原（Mac）　 1962 Van Rood 鉴定出一个新的等位基因系统， 即HLA-B座位　 1969 Amos 发现HLA-D座位 1967 Benacerraf*(1980)和McDevitt 发现并证明Ir基因存在于MHC中　 1970 Sandberg 鉴定出HLA-C座位 1975 Doherty *(1996) 小鼠H-2D、K抗原对Tc杀伤病毒感染 细胞的限制作用 1978 Rosenthal Ir基因产物Ia抗原参与Mφ-T相互作用 1978 Zinkernagel * (1996) MHC对T细胞发育分化的影响 1987 Tonegawa*Ig的基因结构 1990 Murray和Thomas* 肾移植和骨髓移植　　 *诺贝尔奖获得者，括号内为获奖年代

4. PartⅠ Introduction PartⅡ Immunologic mechanism of allogeneic transplantation rejectionPartⅢ Classification and effector mechanisms of allograft rejectionPartⅣ Prevention and treatment of allograft rejectionPartⅤ Exnogtransplantaion contents

5. PartⅠ Introduction • Transplantation: the process of taking cells, tissues, or organs from one individual and placing them into a different individual or different site of the same individual. • Graft: transplanted cells, tissues, or organs. • Donor: the individual who provides the graft. • Recipient: the individual who receives the graft. Also called the host.

6. Autologous graft (Autograft): Syngeneic graft (Isograft ): Allogeneic graft (Allograft): Xenogeneic graft (Xenograft ):

7. autologous transplantation

8. isogeneic transplantation

9. heterogous transplantation

10. Autograft Isograft Allograft Xenograft The most formidable barrier is the immune system. Allograft Rejection Displays Specificity and Memory.

12. (strain C) lymphocytes

13. PartⅡ Immunologic mechanism of allogeneic transplantation rejection • Transplantation antigens • Mechanism of allograft rejection

14. 1. Transplantation antigens • Major histocompatibility antigens (MHC molecules) • Minor histocompatibility antigens • ABO Blood group antigens and tissue specific antigens

15. 2.Mechanism of allograft rejection The immune responses in allogeneic transplantation: • T cell mediated rejection of allograft • Antibody mediated rejection of allograft • NK cell mediated rejection of allograft

16. T Cells Play a Key Role in Allograft Rejection 10 days 3 days 3 days

18. T cell mediated rejection of allograft (mechanism of cellular immunity) 1)Recognition of alloantigens 2)Activation of T cells and rejection of allograft

19. 1) Recognition of alloantigens • Direct recognition ------acute rejection • Indirect recognition ------chronic rejection

20. ① Direct recognition of alloantigens • Recognition of an intact MHC molecule displayed by donor APC in the graft. • An allogeneic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus peptide.

21. Passenger leukocytes The donor APCs that exist in grafts.

22. Fast and strong reaction in acute rejection

23. Direct recognition is a cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus foreign peptide, with an allogeneic MHC molecule (plus peptide). • As many as 2% of an individual’s T cells are capable of directly recognizing and responding to a single foreign MHC molecule.

25. Direct recognition of TCR to allogeneic MHC molecules T cell from recipient CD8+T CD8+T APC from donor CD4+T

26. Direct recognition of TCR to allogeneic MHC molecules T cells from host CTL CTL donor tissue cells

27. ② indirect recognition of alloantigens • the donor MHC molecules may be processed and presented by recipient APCs that enter grafts, and the processed MHC molecules are recognized by T cells like conventional foreign antigens.

28. Indirect recognition of TCR to allogeneic MHC molecules Host T cell CD8+T Host APC CD8+T CD4+T Graft are uptaked by self APC processing Presentation by self APC

29. 2) Activation of T cells and rejection of allograft Host T cells may be activated by both direct recognition and indirect recognition • Direct pathway : CD4+T ---- Th CD8+T ---- CTL ---- killing graft cells • Indirect pathway : CD4+T ---- infiltrate the graft and recognize donor alloantigens being displayed by host APCs that have entered the graft ---- Th CD8+T ---- can not directly kill the foreign cells in the graft

31. T Cells Play a Key Role in Allograft Rejection

32. Difference between direct and indirect allorecognition

33. (2) Antibody-mediated rejection of allograft (mechanism of humoral immunity) Ⅰ ． Complement activated by antibody involved in transplantation rejection Ⅱ.Antibody participate in transplantation rejection through ADCC and opsonization III. Enhancing antibody and transplantation rejection enhancing antibody+transplantation antigen →block other antibodies or T cells binding to antigen. Also called blocking antibody

35. (3)NK cell mediated rejection of allograft • KIR can’t recognize allogeneic MHC of graft • CKs secreted by activated Th cells can promote NK activation.

36. PartⅢ Classification and effector mechanisms of allograft rejection • Host versus graft reaction (HVGR) • Hyperacute • Acute • Chronic • Graft versus host reaction (GVHR)

37. Host versus graft reaction (HVGR) • Hyperacute rejection: • It begins within minutes to 1-2days after host blood vessels are anastomosed to graft vessels. • It is characterized by thrombotic occlusion of the graft vasculature. • It is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens. • ------ Complement activation, endothelial damage, inflammation, thrombosis. • Immune suppression is not effective

39. Host versus graft reaction (HVGR)

40. Acute tubulointerstitial rejection: Mononuclear interstitial infiltrate.

41. Host versus graft reaction (HVGR) • Chronic rejection : • It develops months or years after acute rejection reactions have subsided. • It is characterized by fibrosis and vascular abnormalities with loss of graft function. • The mechanisms of chronic rejection include both humoral and cell-mediated responses . • -------chronic DTH reaction in vessel wall, intimal smooth muscle cell proliferation, vessel occlusion.

42. Chronic Vascular Rejection - Concentric Fibrous Intimal Thickening and Lymphocytic Infiltration

43. Graft versus host reaction (GVHR) BM transplantation Graft versus host diseas (GVHD) GVHD: a disease occuring in bone marrow transplant recipients that is caused by the reaction of mature T cells in the marrow graft with alloantigens on host cells. The diease most often affects the skin, liver, and intestines.

44. PartⅣ Prevention and treatment of allograft rejection ①Reducing the immunogenicity of allografts（tissue typing) ②Immunosuppression ③Inducing donor-specific tolerance

45. ①Reducing the Immunogenicity of allografts: • Donors and Recipients Are Typed for RBC and MHC Antigens Blood group antigens matching MHC matching • HLA-A, B and HLA-DR is important for predicting outcome.

46. Mixed lymphocyte reaction to determine identity of class II HLA antigens between a potential donor and recipient. Lymphocytes from the donor are irradiated or treated with mitomycin C . If the class II antigens on the two cell populations are different, the recipient cells will divide rapidly and take up large quantities of radioactive nucleotides into the newly synthesized nuclear DNA. The amount of radioactive nucleotide uptake is roughly proportionate to the MHC class II differences between the donor and recipient lymphocytes.

47. ②Immunosuppression: • Immunosuppressive drugs that inhibit or kill T cells are the principal treatment regimen for graft rejection. Cyclosporine(CsA), FK506 • Antibodies that react with T cell surface structures and deplete or inhibit T cells are used to treat acute rejection episodes. • Anti-inflammatory agents are also routinely used. • Corticosteroids to block the synthesis and secretion of cytokines.

48. ③Inducing donor-specific tolerance: • Blocking T cell activation • Th2 cytokines • microchimerism

49. PartⅤ Exnogtransplantaion • lack of organs for transplantation. The seriousness of the donor organ shortage is reflected in the fact that, as of November 2000, an estimated 73,000 patients in the United States were on the waiting list for an organ transplantation. The majority of those on the list (~70%) require a kidney; at present, the waiting period for this organ averages over 800 days.

50. Summary • Direct recognition, Indirect recognition • Immunologic mechanism of allogeneic transplantation reject • Classification and effector mechanisms of allograft rejection • Prevention and treatment of allograft rejection