Understanding Transplant Immunology: Graft Compatibility & Rejection

1. Transplantation immunology Dr Adel Almogren.

2. Transfusion vs. Transplantation • Transfusion • transfer of blood • Ab-mediated reactions • Transplantation • transfer of any other tissue/organ • T cell mediated reactions

3. Transplant Immunology Outline • Introduction • Graft compatibility • Graft rejection • Types of organ transplantation

4. Transplant Immunology Outline • Introduction

5. Introduction Transplantation the moving of cells, tissues, and organs from one site to another Graft the transplanted organ Donor person from whom graft is taken Recipient (host) person who gets the graft • 1954 - first transplant (living kidney) • 1960s - liver, heart transplants

6. Introduction • Surgical difficulties • Graft rejection • Organ shortage Transplantation problems

7. Transplant Immunology Outline • Introduction • Graft compatibility

8. Compatibility Rejection = recipient recognizes graft as foreign, and destroys it Autograft within same person Isograft between identical twins Allograft between genetically different people Xenograft between different species

9. Compatibility • Histocompatible: antigenically similar to the host • Histoincompatible: antigenically different from the host • MHC antigens are the most important • ABO antigens are also important • Minor histocompatiblity antigens are less important Histocompatibility

10. Compatibility • Gene collection on chromosome 6 • Three regions: class I, class II, class III • Class I gene products • HLA-A, HLA-B, HLA-C • expressed on nearly all cells • present antigen to TCcells • Class II gene products • DP, DQ, DR • expressed on antigen-presenting cells • present antigen to TH cells HLA complex

12. Compatibility

13. Compatibility • HLA genes sit very close to each other • Inherited as a set (“haplotype”) • Everyone has two sets, one on each ch. 6 • Genes are codominantly expressed (both maternal and paternal gene products are expressed in the same cell) HLA inheritance

14. Compatibility • The more matching alleles between donor and host, the better! • Matching the class II antigens is more important than matching the class I antigens. • One or two class I mismatches = no big deal • One or two class II mismatches = big deal • Mismatches in both class I and II = very big deal HLA inheritance

15. number of mismatches Class I Class II 100 50 graft survival, % 3 6 12 time after transplant, months

16. Transplant Immunology Outline • Introduction • Graft compatibility • Graft rejection

17. 1st set versus 2nd set reactions

18. 1st set versus 2nd set reactions Role of cell mediated responses Unprimed syngeneic recipient

19. Rejection • Any two people (except identical twins) will express some HLA proteins that are different. • Every recipient will recognize, and react against, at least some foreign antigens in the graft • Rejection is complex, with lots of killing mechanisms.

20. Rejection • Direct pathway of recognition • Indirect pathway of recognition How do recipient cells know which cells to kill?

21. Direct Pathway Indirect Pathway

22. Rejection • T-cell-mediated rejection • Antibody-mediated rejection Two mechanisms of rejection

23. Rejection • CD8+ CTLs kill graft cells directly • CD4+ cells trigger a delayed hypersensitivity reaction T-cell mediated rejection

24. Role of CD4+ versus CD8 T+ cells Injecting recip. mice with monoclonal Ab against CD8, CD4 or both to deplete one or both types of T cell

25. Rejection • Hyperacute rejection • Acute rejection • Chronic rejection Clinical types of rejection

26. Clinical manifestations of graft rejection • Hyperacute rejection: very quick • Acute rejection: about 10 days (cell mediated) • Chronic rejection: months-years (both)

27. Rejection Response

28. Transplant Immunology Outline • Introduction • Graft compatibility • Graft rejection • Types of organ transplantation

29. Types of Organ Transplantation • Most common transplanted organ • Diabetes, glomerulonephritis, congenital disorders • Problems: • host sensitization • post-transplant malignancy Kidney

30. Types of Organ Transplantation • Cardiomyopathy, myocarditis, congenital defects, ischemic disease • Must use heart-lung machine • Problems: • organ shortage • maintaining graft before transplant • atherosclerosis • post-transplant lymphoma Heart

31. Types of Organ Transplantation • Leukemia, lymphoma • Find living donor (easy) that matches (hard) • Massive chemo/radiation first • Problem: GVHD Bone marrow

32. Types of Organ Transplantation • Leukemia, lymphoma • Find living donor (easy) that matches (hard) • Massive chemo/radiation first • Problem: GVHD • Donor T cells see recipient as foreign! • Attack skin, GI, liver • Treat with immunosuppressives • Or, partially deplete donor marrow of T cells Bone marrow

33. Tissue Matching

34. General Immunosuppression Therapy

35. Problem 1 A 40 years old man who require a kidney graft due to end-stage renal disease. His HLA genotype was as follows: HLA-A3/A6.B27/B44,CI/C8,DR1/DR4. He brought 5 donors .and tissue typing was performed. Which one of them is the best choice ? Donor no.1 HLA type: HLA-A3/A8, B7/B28, C4/C8, DRI/DR4. Donor no.2 HLA “ : HLA-A6/A6, B27/B24, C12/C1, DR1/7. Donor no.3.HLA “ “ : HLA-A27/A44, B1/B8, C3/C6, DR3/DR14. Donor no.4 HLA “ ‘ : HLA-A3/A6, B24/B7,C2/C9, DR4/DR7. Donor no.5 HLA “ “ : HLA-A3/A3, B27/B44, C1/C8, DR4/DR4.

36. Problem 2 A 5-months old boy who was diagnosed with severe combined immunodeficiency (SCID ) received a bone marrow transplantation from an HLA-matched donor. He was doing well until 2 weeks after transplantation when he developed a skin rash. Subsequently he developed diarrhea, an enlarged liver & spleen and jaundice. What immunological process might be involved in his problem ?

37. Problem 3 A 45-year- old woman with end-stage renal disease due to diabetes mellitus, underwent renal transplantation. She received a kidney from a living, unrelated donor. Approximately one month after transplantation, the patient’s urine output and kidney function decreased. She developed tenderness, pain, and swelling at the graft site. In addition, she had nonspecific symptoms that included fever, decreased appetite, and myalgia (muscle pain).