Lecture 17- Transplantation

1. Lecture 17- Transplantation • Barriers to transplantation • Hyperacute rejection by preexisting antibodies • ABO blood groups • Acute rejection by alloreaction to MHC mismatch • Chronic rejection to major and minor histocompatibility antigens. • The role of MHC matching in graft acceptance • The role for immunosuppressives • Steroids • Cytotoxics • Cyclosporin • Experimental approaches to organ transplantation Reading Parham Chapter 12

2. Figure 12-11 Transplant rejection vs. GvH

3. ABO blood types

4. Blood transfusion Human RBC lack MHC antigens

5. Hyperacute rejection Endothelial cells express ABO antigens

6. Transplanted organs often are stressed and inflamed

7. Hyperacute rejection of a kidney transplant

8. Acute rejection is caused by an alloreactive T cell response Donor (graft) derived dendritic cells ("Passenger leukocytes") can provide potent sensitization of host alloreactive T cells.

9. Acute rejection

10. Time course of skin rejection

11. Genetics of graft rejection

12. Figure 13-39

13. Direct and indirect presentation of alloantigens

15. Major inhistocompatibility vs. minor inhistocompatibility Figure 12.17

16. What are minor histocompatibility antigens? Figure 12.18

17. Chronic rejection

18. Acute kidney graft rejection Lymphocytes surrounding an arteriole Lymphocytes surrounding a renal tubule T cells (CD3) surrounding a renal tubule

19. Antibodies can also participate in chronic rejection.

20. Figure 12-20

21. Figure 12-22 Histocompatibilty and graft survival

22. Immunosuppression using corticosteroids Natural compound drug metabolite

23. Steroid receptors

24. Activity of corticosteroids

25. Cytotoxic drugs Often used in cancer chemotherapy, they tend to kill proliferating cells, including activated lymphocytes.

26. Effect of CsA on graft survival

27. Figure 12.27 Cyclosporin A and FK506 Activation of the IL-2 gene and other genes leads to clonal expansion of the T cell No activation of transcription

28. Figure 12-28 Effects of cyclosporin A Cyclosporin A is the major drug used to overcome graft rejection

29. Tissue transplants

30. Long term approaches to prolong graft survival • Use of xenografts from genetically engineered animals (pigs). Many problems: currently people are working on eliminating the blood group type hyperacute rejection barriers by modifying the glycosyl transferase activity. Advantage: potentially unlimited availability of organs. • Induction of antigen specific tolerance by suppressing costimulation. • Introduction of graft-specific regulatory T cells.

31. Previously activated, “memory” T cells can stimulate unactivated APC using CD40L, leading to the upregulation of B7 molecules. Such APC can perpetuate T cell activation in graft rejection. IL-12

32. New techniques in the treatment of graft rejection

33. An example of the experimental use of antibodies to suppress graft rejection and to promote long term graft tolerance.

34. Concepts • Choice of donor in transplantation is important • ABO blood group matching prevents hyperacute rejection. • MHC matching minimizes acute and chronic rejection. • Several immunological barriers to transplantation • Preexisting antibodies • Passenger dendritic cells from graft • Major and minor histocompatibility antigens • Ultimately, immunosuppression is important to promote graft acceptance. • Role of corticosteroids, cytotoxic compounds and inhibitors of calcineurin. • There is much room for improvement in immunosuppressives, especially specificity and the ability to promote graft tolerance. Next time: Vaccines and preview of final