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Transplantation Immunology

Transplantation Immunology. 中国科学院上海生命科学研究院 / 上海交通大学医学院 健康科学研究所 上海市免疫学研究所 张雁云. 1. Section I: Allogeneic transplantation rejection. 2. Section II: Types of rejection. 3. Section III: Prevention and treatment. 4. Section IV: Relative immunity. Contents. 公元 4 世纪. 罗马教堂. Long long ago….

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Transplantation Immunology

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  1. Transplantation Immunology 中国科学院上海生命科学研究院/上海交通大学医学院 健康科学研究所 上海市免疫学研究所 张雁云

  2. 1 Section I: Allogeneic transplantation rejection 2 Section II: Types of rejection 3 Section III: Prevention and treatment 4 Section IV: Relative immunity Contents

  3. 公元4世纪 罗马教堂 Long long ago…

  4. I: cellular tissue transplantation organ II: autologous syngeneic allogeneic xenogeneic transplantation Transplantation • Types of transplantation

  5. Transplantation

  6. Milestone 1956 1956first successful bone marrow transplantation1969 relatives 1977 unrelated

  7. Transplant immunity “laws” of transplantation: • Autogeneic grafts survive • Syngeneic grafts survive • Allogeneic grafts are rejected • Parent-to-F1 grafts survive • F1-to-parent grafts are rejected • Xenogeneic grafts are rejected In an allogeneic graft, donor and recipient cells should have very similar types of surface antigens. So, why are allogeneic grafts always rejected?

  8. Section I Allogeneic transplantation rejection Graft rejection is an immune response

  9. Section I

  10. MHC MHC alleles are major targets of immune response Recipient T cells cross-react with donor MHC ( Ag) • Selected for biding to self MHC + Ag peptide • Foreign MHC may “look” like self + Ag Section I Alloantigen

  11. Target=MHC Section I Alloantigen

  12. Gender relative mH Ag，性别相关的mH抗原 • Autosome codogenic mH Ag，常染色体编码的mH抗原 • Recognized by CTL/Th cell with MHC restriction, • but can not directly recognized by T cell • Can be presented by different types of HLA molecules • Different predominate mH in different transplantation cases • Single mH mismatch cause “slow” rejection, • but multiple mH mismatch can also cause “fast” rejection Section I Alloantigen Minor MHC

  13. Target=miMHC Section I Alloantigen

  14. 人类ABO血型抗原 超急性移植排斥反应 组织特异性抗原 VEC SK Section I Alloantigen Other antigens:

  15. Transplantation Alloantigen presentation

  16. Section I Alloantigen presentation Two Types of Alloantigen Presentation Direct & Indirect

  17. Fast and strong Section I Alloantigen presentation Direct presentation of alloantigens 供者APC将其表面的MHC分子或抗原肽-MHC分子复合物直接提呈给受者的同种反应性T细胞，供其识别并产生应答，而无需经受者APC处理。

  18. Recipient lymphocytes Can’t proliferate + Compatible donor lymphocytes + 3H thymidine No proliferation Low radioactivity in cells + Incompatible Donor lymphocytes + 3H thymidine Proliferation High radioactivity in cells Section I Alloantigen presentation MLR evidence for direct presentation

  19. Section I Alloantigen presentation Mechanism for direct presentation TCR 识别抗原肽和MHC分子的复合结构（pMHC） 记忆T细胞可能是参与交叉反应的主要效应细胞

  20. Section I Alloantigen presentation Mechanism for direct presentation

  21. Section I Alloantigen presentation Indirect presentation of alloantigens 受者APC加工和处理供者抗原，提呈给受者T细胞，使之活化

  22. 效应机制 Allorecognition and effect mechanism Direct and indirect allorecognition

  23. Effect Mechanism Cellular Immunity——Against graft T cell activation

  24. Section I Effect Mechanism Humoral Immunity——Against graft B细胞激活，分化，浆细胞，分泌特异性抗体 调理作用、免疫黏附、ACDD、CDC NOTE：抗体在急性排斥反应中不起重要作用

  25. 机械性损伤、缺血、 缺氧、再灌注损伤 同种器官移植 炎性“瀑布式”反应（炎症细胞活化） 非特异性效应分子释放： 炎性细胞因子释放； 体液中异常激活的级联反应系统 （补体、凝血系统等） 树突状细胞成熟 启动同种特异性排斥反应 移植物组织细胞炎症、损伤和死亡 Section I Effect Mechanism 非特异性效应机制

  26. Section II Types of rejection

  27. Types of rejection Host versus Graft Reaction HVGR

  28. 超急性排斥反应 血管吻合接通后24小时 移植器官功能迅速衰竭 唯一治疗措施是再移植 急性排斥反应 突然发生寒战、高热，移植物肿大引起局部胀痛 移植后4天至2周 慢性排斥反应 免疫抑制药物治疗常难凑效 移植术后数月至数年 临床排斥反应综合征

  29. Within minutes of transplantation • Results from recipient’s pre-existing, circulating Ab • Ab binds donor Ag in transplanted tissue blood vessels • Clotting and complement mechanisms activated • Death of transplanted tissue due to lack of oxygen Section II HVGR Hyperacute rejection

  30. Within days of transplantation • CMI response to donor MHC (CTLs attack donor tissue) • Ab response also contributes Section II HVGR Acute rejection

  31. Normal Glomerulus 肾移植物中的急性排斥反应 HE Immunoflourescence of Abs

  32. 心脏移植物中的急性排斥反应 Anti-CD3 Peroxides Stain of T cells in Myocardium

  33. Months to years after transplantation • Slow, progressive loss of function • Proliferation of fibroblasts and vascular cells • Probably due to cytokines secreted by alloreactive T cells Section II HVGR Chronic rejection Chronic allograft dysfunction, CAD

  34. renal artery interstitial fibrosischronic inflammation 肾移植物中的慢性排斥反应

  35. Section II HVGR Factors in Chronic Rejection

  36. Section II HVGR Summary

  37. Types of rejection Graft versus Host Reaction GVHR

  38. Section II GVHR • 特定条件 • 受者与供者之间MHC不合 • 移植物含有足够数量的免疫细胞 • 受者处于免疫无能或免疫功能严重缺陷状态

  39. Section II GVHR Overview of GVHD

  40. Section II GVHR GVLR 骨髓移植物中的供者免疫细胞向残留的白血病细胞发动攻击， 从而防止白血病复发。

  41. 受者体内出现特异性识别白血病细胞的供者T细胞克隆受者体内出现特异性识别白血病细胞的供者T细胞克隆 • DLI诱导调节性T细胞，抑制GVHD发生 • 激活的供者淋巴细胞产生某些细胞因子， • 诱导白血病细胞高表达Fas抗原 Section II GVHR DLI诱导GVLR的机制：

  42. 缺少血管和淋巴管，淋巴细胞不能接触移植物抗原缺少血管和淋巴管，淋巴细胞不能接触移植物抗原 • 存在特殊的屏障 • 免疫原性弱 • 赦免区组织细胞高表达FasL Section II 排斥反应的特殊情况 免疫赦免区

  43. 红细胞血型检查 • 受者血清中细胞毒性预存HLA抗体测定 • HLA分型 • 交叉配型 • 次要组织相容性抗原型别鉴定 Section III Preventing rejection 供者的选择

  44. Depletion of T cells Section III Preventing rejection 移植物和受者的预处理

  45. 免疫抑制剂 • 清除预存抗体 • 其他免疫抑制方法 Section III Preventing rejection 抑制受者的免疫应答

  46. 免疫抑制剂

  47. 免疫抑制剂

  48. 淋巴细胞亚群百分比和功能测定 • 免疫分子水平测定 Section III Preventing rejection 移植后的免疫监测

  49. Section IV移植相关的免疫学问题 诱导同种移植耐受 • 骨髓移植中建立同种异基因嵌合体（建立同种异基因造血干细胞嵌合体、混合嵌合体） • 阻断针对移植物（或宿主）的特异性免疫应答 • 阻断共刺激通路诱导同种异型反应性细胞失能（CTLA-4Ig融合蛋白、抗CD40L单抗） • 非特异性抑制炎症应答（IDO、HO） • 主动免疫诱导同种移植耐受 • 借助树突状细胞诱导T细胞失能 • 定向调控Th细胞分化 • 阻断效应细胞迁移 • 其他策略

  50. For example

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