Ch. 17. Transplantation Immunology What is graft rejection? How is graft rejection controlled? What is the status of tr

1. Ch. 17. Transplantation Immunology What is graft rejection? How is graft rejection controlled? What is the status of transplantation? Barriers surgical availability immune response Ch. 17

2. First successful human kidney transplant- 1954 Many organs have been transplanted successfully Key insight came from blood group work (notion of incompatibility) Medawar, 1940s- graft rejection is immune reaction autografts are accepted, allografts are not second grafts are rejected more rapidly than the first (memory) Discovery of MHC arose from transplant work Ch. 17

3. Current goals: minimize graft rejection (demand is high, availability of genetically identical donors is low) Minimize rejection without suppressing entire immune response Ch. 17

4. Types of grafts Autograft- within same individual Isograft- from genetically identical donor Allograft- from genetically different member of the same species Xenograft- from a different species future: transgenic species? Ch. 17

5. p. 427 Ch. 17

6. p. 428 Ch. 17

7. p. 428 Ch. 17

8. Many antigens determine histocompatibility MHC antigens produce most vigorous rejection response Mouse haplotype b/b and k/k produce a b/k offspring (inbred mouse strains) Offspring can accept graft from either parent Neither parent can accept graft from offspring Ch. 17

9. Outbred populations: Chance of match between (full) siblings is about 25% How to determine if donor and recipient are compatible? Blood groups must match blood group antigens are also found on endothelium of blood vessels (part of donor tissue) Microcytotoxicity test Ch. 17

10. p. 429 Ch. 17

11. Ch. 17

12. Ch. 17

13. p. 430 Ch. 17

14. Identity at MHC Class I and Class II is not the whole story MHC differences may be recognized directly by T cells (alloreactivity) Other antigens must be presented Ch. 17

15. Mechanisms of graft rejection Sensitization Dendritic cells in graft may act as APCs Host effector cells can migrate Donor cells can migrate to periphery and present graft antigens there Other cells may act as APCs Ch. 17

16. Varies with the graft Effector cells are usually produced in the lymphoid tissue and then circulate back to graft Skin- vasculature restored gradually Kidney or heart- immediately Some sites (e.g., eye) do not encounter immune cells Ch. 17

17. p. 432 Ch. 17

18. p. 453 Ch. 17

19. Clinical aspects of graft rejection Hyperacute- within 24 hours graft is never vascularized preexisting antibodies (complement) Crossmatching to prevent this Acute- within a few weeks TH cell activation Chronic- a long time later humoral and cell-mediated an intractable problem Ch. 17

20. Immunosuppressive therapy Most drugs are nonspecific Other rapidly-dividing cells are affected (epithelial cells, bone marrow cells) Mitotic inhibitors- azothiaprine, methotrexate Corticosteroids- anti-inflammatory More specific inhibitors cyclosporin A, FK506- inhibit T cell activation Rapamycin- blocks TH proliferation Ch. 17

21. Cyclosporin A was the breakthrough Other drugs are newer less toxic to kidneys effective at lower doses TLI- total lymphoid irradiation recipient’s lymphoid tissues are irradiated before grafting bone marrow is not; repopulating cells seem to be more tolerant Ch. 17

22. p. 436 Ch. 17

23. Immune therapy Monoclonal antibodies that block T cell response To surface proteins high-affinity IL-2 receptor TCR-CD3 or accessory molecules adhesion molecules looking for anergy To cytokines To co-stimulatory signal might target activated T cells more specifically (TH and APC) Ch. 17

24. p. 438 Ch. 17

25. Ch. 17

26. p. 439 Ch. 17

27. p. 440 Ch. 17

28. Clinical cases • Kidney • most common; easier surgically than some • the donor survives • Transplant recipients are sensitized to further • transplants Ch. 17

29. II. Bone marrow Recipient is immunosuppressed before graft Graft-vs-host disease is common (50-70%) TNF- is a major player Possible treatments immunosuppression donor T cell depletion (partial; some activity needed against host T cells) Ch. 17

30. III. Heart surgery is quite successful MHC matching is often not feasible; massive immunosuppression transplants seem to be prone to coronary disease IV. Lungs sometimes go with heart transplants are still rare V. Liver- parts have been grafted successfully resistant to antibody mediated toxicity but not GVHD relatively difficult surgery Ch. 17

31. VI. Pancreas- functional parts (islet cells) still rare VII. Skin- usually autologous burn victims- tissue bank donors have been used. immunosuppression is a problem because a burn patient is vulnerable to infection Ch. 17

32. p. 443 Ch. 17

33. VIII. Immunologically privileged sites Some areas not infiltrated by immune cells cornea, brain, uterus, testes thymus? What about sequestering donor tissue from host immune system? e.g., islet cells in semipermeable membranes worked in mice Ch. 17

34. VIII. Xenotransplantation- promising but controversial Better to meet the demand? Nonhuman primates- have not been particularly successful, and not that common anyway Transgenic pigs organs are similar size and structure are being engineered to have human antigens and/or immunosuppressive capacities can be bred in large numbers and under controlled conditions Ch. 17

35. Drawbacks success of graft is not proven appropriate use of these animals? risk of spreading zoonoses (animal-borne diseases) to human recipients? development of new pathogens? should we be doing this? Ch. 17

36. Why is the fetus not rejected? • “Protected” site • Local immunosuppression • uterine epithelium and trophoblast* secrete • cytokines that suppresses TH1 • placenta secretes a substance that depletes • tryptophan: T cell starvation? • tolerance of paternal MHC antigens? • *Outer layer of placenta; does not express MHC • Class I and Class II antigens Ch. 17