Transplantation Immunology

1. Transplantation Immunology Nehal Draz

3. Graft TypesI- Based on foreigness • 1- Autograft: from one area to another, same inbividual, NO IR • 2- Syngraft (Isograft; Syngeneic): genetically identical individuals, NO IR, Histocompatible • 3- Allograft (commonest) two genetically dissimilar individuals, same species, Histoincompatible & rejection • 4- Xenograft: donor & recipient from different species Histoincompatible & rejection

5. II- According to origin • Living graft: from a living donor,e.g. liver segment, kidney, BM • Cadaveric graft: from a recently dead individual,e.g. heart, cornea, liver, kidney

6. III- According to immunogenecity • Bone marrow is the most immunogenic • Liver is the least immunogenic depending on: • Privileged sites: e.g.cornea No significant IR 1- Lack of suitable APCs In some tissues 2- Different expression of HLA molecules Lack of lymphatic drainage

7. The Major Histocompatibility (MHC) HLA

8. MHC Refers to genes encoding HLA proteins MHC molecules Refers to the protein HLA

9. Allelic polymorphism: • The MHC genes represents the most polymorhic genetic system • Multiple different allels of the same gene exist in the human population • Different allels of the same gene can give Ags with slightly distinct sequences e.g. A gene has 151 allels

10. Functions of MHC • 1- control IR by MHC restriction • 2- targets of IR resulting in cytotoxity in graft rejection • 3- Certain MHC allels are associated with some diseases e.g. multiple sclerosis &DR2

11. IR to transplantsI- Sensitization phase • Recipient Tcells can recognize donor allo Ags in the graft by 2 different ways:

12. A. Direct allorecognition • Recipient Tcells recognize donor;s Ags on donor's MHC molecules on the graft APCs • Donor APCs leave the graft & migrate to the regional lymph nodes • There they activate recipient’s Tcells • The activated Tcells are carried back to the graft which they attack directly

13. B. Indirect allorecognition • Uptake of donor MHC molecules by the recipient own APCs and presentation to self Tcells on self MHC molecules

14. II- Effector phase CD8 Tcells - The generated alloreactive CTLS attack graft cells bearing MHC I and destroy them by direct cytotoxicity C M I CD4 Tcells • Secrete cytokines enhancing graft damage: • - IL-2: stimulate CTLs • IFNγ: increase allogenic MHC class I &II on graft cells • IL4, 5, 6 stimulate Ab production by Bcells

15. HUMORAL Y Foreign GRAFT cell IgG or IgM MQ destruction NK 3- ADCC 1- Opsonization 2- Complement mediated lysis effector phase. cont

16. Mechanisms of Graft Rejection • 1- Hyperacute rejection • 2- acute rejection • 3- Chronic rejection

17. 1- Hyperacute rejection • Within minutes • Circulating preformed anti ABO or anti-HLA antibodies • Activation of compl. and clotting pathways • No treatment • Prevention: proper matching

18. 2- Acute rejection • Within days or weeks • Treatment: immunosuppression • Prevention: proper matching TC Destroy graft cells CD4 Lymphokines activating Infl.& MQ YYYY Endothelial injury

19. 3- Chronic rejection Delayed type hypersensitivity Alloantigen in Vessel wall CYTOKINES • After months or years • No treatment • Prevention: proper matching Proliferation of smooth Muscle cells Gradual lumen narrowing ischemia, Interstial fibrosis Loss of function

20. Prevention of graft rejection Histocompatibility testing Recipient preparation Post-operative immunosuppressive therapy

21. I- Histocompatibility testing 1- ABO typing 2- HLA testing: determination of HLA phenotype for donor & recipient which can be done by: a) microlymphocytotoxicity test b) HLA molecular typing: PCR c) white cell cross matching: mixed lymphocytotoxicity test 3- detection of preformed Abs against donor cells in the serum of the recipient

22. II- Recipient preparation • Complete history taking & full clinical examination • Treatment of hypertension if present • Treatment of infections if present • Prophylactic antibiotics • Pre-transplantation immunosuppressive therapy

23. III- Post-operative immunosuppressive therapy • The drugs used to suppress the immune system can be divided into 3 categories: Powerful anti-inflammatory drugs (corticosteroid) prednisone Cytotoxic drugs • Azathioprine • Cyclophosphamide Fungal & bacterial derivatives • Cyclosporine A • FK506 • Rapamycin

24. Common immunosuppressive drugs

25. Complications of post- operative immunosuppression • Infections • Malignancies: especially lymphomas & carcinoma of the skin • Anaphylaxis or serum sickness • Graft verus host disease (GVHD)

26. Bone Marrow Transplantation (BMT) • A successful therapy for tumors derived from marrow precursors such as leukemia & lymphomas • It may be also successful in treatment of some primary immunedefficiency disease such as severe forms of thalassemias

27. Special problems associated with BMT • In leukemia therapy, the source of leukemia must be first destroyed by aggressive cytotoxic chemotherapy. The patient is thus severely immunocompromised • Bone marrow cells are highly immunogenic& can elicit a strong IR • Therefore, very careful donor/recipient HLA matching is critical

28. If mature donor Tcells are transplanted with the marrow cells, these mature Tcells recognize the tissues of the recipient as foreign causingsevere inflammatory disease called: • Rashes • Diarrhea • Pneumonitis • Liver dysfunction • Wasting • Death GVHD Graft Versus Host Disease

29. Strategies for preventing graft rejection & GVHD following BMT 1- The most crucial factor is donor selection &MHC compatibility: an identical twin is the ideal donor 2- From poorly matched grafts, T lymphocytes can be removed using monoclonal Abs. to avoid induction of an immune response by the immune competent (mature) donor Tcells against the tissues of the immunocompromised recipient & hence GVHD

30. 3-Malignant cells should be eliminated from the recipient blood to avoid recurrence of the underlying malignancy which necessitated the BMT in the first place 4- Methotrexate, cyclosporin & prednisone are often used to control GVHD

31. Thank you!!