Immunology of Transplantation & Malignancy

1. Immunology of Transplantation & Malignancy Dr. Sudheer Kher

2. Why do we need to transplant? • Basically to restore function when • Organ or tissue is irreparably damaged as a result of disease or injury. • An organ or tissue is congenitally absent or defective. • Transplant or Graft -Tissue or organ that is transplanted. • Donor - The individual from whom tissue or organ is taken. • Recipient - The individual in whom the tissue or organ is applied.

3. Historical • Mankind’s ancient dream. • Ancient nation’s mythologies always talk of some kind of transplantation across species • Skin grafting technique using patient's own skin to reconstruct severed nose described in Shushruta Samhita (800 BC). • Transplantation of Elephant head – Lord Ganesha. • 1940 – Medawar conclusively proved immunological basis of rejection of exogenous grafts.

5. Basis – Organ / Tissue transplanted Kidney Transplant Heart Transplant Skin Transplant Basis – Anatomical site of origin / destination of transplant Orthotopic – Normal site Heterotopic – Abnormal site Classification of Transplants

6. Basis – Freshness Fresh graft Stored graft Basis – Whether live or dead Vital grafts e.g. kideney Static or Structural grafts e.g. Artery, Bone. Basis – Immunological-Genetic & Antigenic relationship between donor & recipient. Autograft – Self graft Syngeneic / Isograft – Same genetic constitution e.g. identical twins Allograft – Same species but different genetic constitution. Xenograft – Different species. Classification of Transplants

7. The allograft rejection – The First set response. • When skin from rabbit is applied to another genetically unrelated animal – • Initially the graft is accepted. Vascularization starts. Remains healthy for 2-3 days. • By 4th day, inflammation starts, Lymphocytes and Macrophages invade. BVs occluded by thrombi, vascularity diminishes, ischemic necrosis sets in. Graft changes to scab -> sloughed off by 10th day. • This is called ‘first set response’.

8. The allograft rejection – The Second set response. • If, in an animal, which has rejected a graft by first set response, another graft from the same donor is applied – • The graft is rejected in an accelerated manner. • Vascularization is attempted but is soon interrupted by inflammatory response. Necrosis sets in early, graft is sloughed off by 6th day. • This accelerated allograft rejection is called ‘second set response’.

9. Mechanism of allograft rejection • Basis immunological. • Clear from specificity of second set response. • Accelerated rejection seen only if the second graft is from the same donor as the first. • Application of skin graft from another donor evokes only the first set response. • Allograft accepted if the recipient animal is made immunologically tolerant. • If splenic cells of the donor are injected into recipient fetal or neonatal animal, they will accept the graft at a later time. This is due to specific immunological tolerance

10. Mechanism of allograft rejection • Transplantation immunity is predominantly CMI. • First set response almost exclusively by T cells. • Humoral antibodies are also produced. They have some role in second set response. • Hyperacute rejection – • If transplantation is attempted in animals having high titre of antibody against graft antigens, the graft remains pale and is rejected in matter of hours. This is also called as ‘White graft response’. • Seen in human kidney transplantation when there is high antibody titre due to previous transplantation, blood transfusion or pregnancies.

11. Immunological enhancement • Humoral antibodies may sometimes act against CMI, by inhibiting graft rejection. • If recipient is pretreated with one or more injections of killed donor tissue and the transplant applied subsequently, the graft survives longer than in control animals. This effect can be passively transferred by injecting antibodies. • Mechanism – • Ab may combine with Ag released from the graft, thus inhibiting initiation of immune response. (Afferent) • Ab may combine with lymphocytes of appropriate specificities and by negative feedback mechanism stop response (Central). • Surface of graft cells may be coated by Ab thus preventing sensitized lymphocytes coming in contact with them. (Efferent)

12. Allograft immunity is a generalized response directed against ALL antigens of the donor.A recipient sensitized by a skin graft will reject by second set response not only another skin graft but also any other organ / tissue graft from the same donor.

14. Transplantation in F1 hybrids BB AA Transplantation Fails Transplantation Successful AB AB

15. Unilateral Sex linked histoincompatibility XX XY Transplantation Successful Transplantation Fails XX XY

17. Blood group matching HLA matching Mixed Lymphocyte Reaction (MLR) Immuno suppression Privileged site transplants Cartilage Brain Testes Cornea Immuno suppression Experimental animals Neonatal thymectomy Chronic lymphatic drainage Administration of ALS Clinical situation Steroids Azathioprene Cyclosporin A Repamycin FK-506 How to make a graft survive?

18. Graft Versus Host Reaction (GVH) • Graft mounting immune response to the antigens of the host. • Occurs when • Graft contains immunocompetent cells • Recipient possesses transplantation Ag that are absent in graft • The recipient must not reject the graft

19. Situations leading to GVH • Allograft in a recipient in whom specific immunological tolerance has been induced • Adult lymphocytes injected into immunologically deficient recipient. Immunodeficiency could be due to immaturity (newborn) or suppression (drugs) • F1 hybrid receiving transplant from any parent strain

20. Clinical Features of GVH in Animals • Retardation of growth • Emaciation • Diarrhea • Hepatpsplenomegaly • Lymphoid atrophy • Anemia • Death • Syndrome is called Runt Disease

21. Immunology of Malignancy • When a cell undergoes malignant change • Acquires new antigens • May lose some normal antigens • The tumor is therefore antigenetically “different” than normal tissue and considered as allograft and accordingly meets with immune response.

22. Evidence for immune reactivity to tumors • Tumors that have severe lympho-reticular infiltration have a better prognosis than those that do not.  • Certain tumors regress spontaneously (e.g., melanomas, neuroblastomas).  • There is an increased incidence of primary and secondary malignancies (particularly lympho-reticular tumors) in immunodeficient patients).  • Antibodies and immune T lymphocytes (in cytotoxicity and mitogenic response assays) have been detected in patients with tumors.  • The young and the very old have an increased occurrence of tumors. These members of the population often have an immune system that is less effective. • Finally, animals can be specifically immunized against various types of tumors.

23. Tumor Antigens • Present in malignant cells but absent in corresponding normal cells. • Present in cell membrane. Called as • Tumor Specific Transplantation Antigens (TSTA) or • Tumor Associated Transplantation Antigens (TATA) • In chemically induced tumors, TSTA is tumor specific while in virus induced tumors TSTA is virus specific.

24. Reappearance of Fetal Antigens • Found in embryonic & malignant cells but not in normal adult cells • Alpha fetoproteins in malignant hepatomas • Carcinoembryonic antigens in colonic cancers • Used for diagnostic purposes

25. Immunity against tumors • Evidence mostly from experimental tumors, although there is ample evidence for anti-tumor immune reactivity in humans. • In experimental studies, animals can be immunized by administering inactivated tumor cells or by removal of a primary tumor. • Also, immunity can be transferred from an animal, in which a tumor has regressed, to a naive animal by injection of lymphocytes (T cells). • All components of the immune system (non-specific and specific; humoral and cellular) can affect the growth and progression of a tumor.

26. Escape from immuno-surveillance • Tumors may not express neo-antigens that are immunogenic or they may fail to express co-stimulatory molecules for the activation of T-cells. In addition, certain tumors are known to lack or be poor expressers of MHC antigen • The amount of antigen may be too small to stimulate the immune system and, due to the rapid proliferation of malignant cells, the immune system is quickly overwhelmed

27. Escape from immuno-surveillance • Some tumors may evade the immune system by secreting immunosuppressive molecules • Others may induce suppressor cells. • Also, some tumors may shed their unique antigens which block antibodies and T cells from reacting with malignant cells. “Smokescreen” mechanism.

28. The way ahead for cancer therapy • Integrated approach • Surgery • Radiotherapy • Chemotherapy • Immunotherapy