TRANSPLANTATION AND TUMOUR IMMUNITY (1).pptx

Transfer of cells, tissues or organs from one individual to another or from one site in the same individual is known as Transplantation.
Graft rejection is due to the reaction of the host to the grafted tissue (host-versus-graft response).

1. TRANSPLANTATION AND TUMOUR IMMUNITY Dr. Faria Ashraf Asst Professor

2. Transfer of cells, tissues or organs from one individual to another or from one site in the same individual is known as T ransplantation. The individual from whom the transplant is obtained is known as Donor . T he individual to whom it is applied is known as R ecipient. TRANSPLANTATION

3. Autograft : organ or tissue taken from one person and grafted on the same person. Isograft : a graft taken from an individual and introduce into another individual of the same genetic constitution. Eg . Identical twins. Allograft (homograft): graft between two genetically non-identical members of the same species. Xenograft (heterograft): graft between members of different species. Cadaver organ transplant Classification of Transplant

4. Primary function of the immune system is to recognise and eliminate foreign cells and antigens that enter the body. Tissues and organs grafted from one individual to another member of the same species (allograft) are recognised as foreign and rejected. The name ‘ histocompatibility complex’ came to be because its discovery was based on transplantation . Major Histocompatibility Complex (MHC)

5. Human MHC antigens are therefore synonymous with human leukocyte antigens (HLA). MHC complex is a system of cell antigens that are responsible for allograft acceptance or rejection. MHC ( contd ….)

6. First Set Response Skin graft from a genetically unrelated animal of same species Initial acceptance first 2-3 days, by about fourth day inflammation and graft is invaded by lymphocytes and macrophages. Thrombosed and necrosed Mainly by T lymphocytes By 10 th day graft sloughs off. The Allograft Reaction

7. Second Set Response If an individual has rejected a graft by the first set response, another graft from the same donor is applied – rejected in an accelerated manner. Necrosis sets early and graft sloughs off by 6 th day. Mainly by antibodies and cell mediated immunity .

8. Hyperacute rejection Acute rejection Chronic rejection Effector Mechanism of Allograft Rejection

9. WHITE GRAFT RESPONSE Pre-existing specific antibodies in high titres in the host circulation bind to donor endothelial antigens on the donor tissue or organ. Activates Complement Cascade Characterized by thrombotic occlusion of graft Graft remains pale Rejected within minutes or hours, even without an attempt at vascularization. Examples : P revious transplantation, blood transfusion or pregnancy. Hyperacute Rejection

10. 1. Preformed Ab , 2. complement activation, 3. neutrophil margination , 4. inflammation, 5. Thrombosis formation Hyperacute Rejection

11. Rejection occur within a week to 10 days after a transplant has been grafted. This type of rejection is due to incompatibility of allograft. The immune response against the graft increase in intensity, with the accumulation of lymphocytes, plasma cells, macrophages and neutrophils, leading to endothelial damage. There is necrosis and edema and finally graft rejected. Cell mediated immunity plays a role in this type of rejection. Acute Rejection

12. T-cell, macrophage and Ab mediated, myocyte and endothelial damage, Inflammation Acute Rejection

13. Occurs in most solid organ transplants Heart , Kidney, Lung, Liver Characterized by: fibrosis vascular abnormalities loss of graft function over a prolonged period rejection occur after 60 days or more. Both humoral and cell mediated immunity plays a role in this type of rejection. Such patients respond poorly to corticosteroids. Chronic Rejection

14. MECHANISM OF GRAFT REJECTION 14 Graft rejection is caused principally by a T cell-mediated immune response to alloantigens expressed on the graft cells, primarily the MHC molecules. Peptides present in the groove of allogeneic: Class I MHC molecules - derived from proteins synthesized within the allogeneic cell. Class II MHC molecules – are proteins taken up and processed by the allogeneic APCs.

15. MECHANISM OF GRAFT REJECTION (Cont..) 15 The process of graft rejection can be divided into two stages: Sensitization phase- which involves alloantigen (mainly graft MHC molecules) presentation to recipient’s T cells Effector stage - which immune destruction of the graft takes place due to activation of recipient’s T cells.

16. Mechanisms involved in graft rejection

17. Graft rejection is due to the reaction of the host to the grafted tissue ( host-versus-graft response ). The graft mounts an immune response against the antigens of the host. This is known as the graft versus host reaction. This is common in stem cell therapy in bone marrow transplants. GVH disease is of 2 types- Acute: within 100 days after transplantation Chronic: after 100 days of transplantation. They are graded on the basis of the severity and tissue affected. Graft versus Host Reaction

18. The recipient possesses transplantation antigens that are absent in the graft. The graft contains immunocompetent T cells. The recipient is incapable of mounting an effective response to eliminate the graft immunocompetent cells. GVH occurs under the following conditions:

19. The acute or fulminant form of the disease (GVH) is normally observed within first 10- 100 days post transplant. GVH reactions are predominantly cell mediated. The manifestations of GVH reaction consist of splenomegaly, fever, rash, anaemia,weight loss and sometimes death. Neonatally thymectomisd animal receiving an allograft of spleen or blood lymphocytes do not grow normally but develop a fatal wasting syndrome.This syndrome is known as Runt disease .

20. 1. Histocompatibility Testing: Blood grouping : ABO Blood group compatibility. HLA compatibility: -HLA typing - Microcytotoxicity test -Molecular methods RFLP with southern blotting PCR using sequence specific primers 2. Tissue Matching : -mixed lymphocyte reaction or culture Laboratory Test R equired B efore Transplantation

21. Prevention of Graft Rejection:- Immunosuppressive Therapy 22 Hyperacute rejection manifests severely and within minutes, and so the treatment indicated is- immediate removal of the tissue. Chronic rejection is generally considered irreversible and poorly amenable to treatment—only re-transplant generally indicated if feasible—though inhaled cyclosporine is being investigated to delay or prevent chronic rejection of lung transplants.

22. Immunosuppressive Therapy (Cont..) 23 Acute rejection is treated with therapeutic regimens consisting of one or combination of various immunosuppressive therapies .

23. Immunosuppressive agents used to improve graft survival 24 Immunosuppressive drugs: Corticosteroids Prednisolone, hydrocortisone Calcineurin inhibitors Cyclosporine, Tacrolimus Mitotic inhibitors Azathioprine Cyclophosphamide Methotrexate Anti- proliferatives Mycophenolic acid mTOR inhibitor (mammalian target of rapamycin) Sirolimus (rapamycin) Everolimus

24. TUMOUR ANTIGENS 25 Two types of tumour antigens have been identified on tumor cells: Tumour-specific transplantation antigens (TSTA) Tumour-associated transplantation antigens (TATA)

25. Tumour -specific Transplantation Antigen 26 Tumour-specific antigens are present only on tumour cells and are absent in normal cells of the body. May result from mutations in tumour cells that generate altered cellular proteins. Such tumour specific antigens reject tumour transplants in immunised hosts, these are termed as tumour specific transplantation antigens.

26. Tumour -specific Transplantation Antigen (Cont..) 27 TSTA are induced on tumour cells either by chemical or by physical carcinogens, and also by viral carcinogens. Tumour specific. Methyl cholanthrene and ultraviolet light are the examples of chemical and physical carcinogens that are extensively studied.

27. Tumour -specific Transplantation Antigen (Cont..) 28 In contrast, the TSTA of virus induced tumours is virus specific; all tumours produced by one virus would possess the same antigen. Example: nasopharyngeal carcinoma and several types of lymphoma caused by Epstein Barr virus .

28. Tumour -associated Transplantation Antigens 29 Not unique to tumour cells and may also be expressed by normal cells . Their level gets exponentially high in tumour cells.

29. Tumour -associated Transplantation Antigens (Cont..) 30 Oncofetal antigens - proteins that are expressed on normal cells during fetal life but not expressed in the adult normally. Reactivation of the embryonic genes that encode these proteins in tumour cells results in their expression on the fully differentiated tumour cells. Examples include alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA ). Non- oncofetal TACAs : Examples include Carbohydrate antigens (CA 125, CA 19-9), prostate specific antigen (PSA).

30. TATAs used as tumor markers for diagnosis of cancers 31 Tumor markers Tumor types Oncofetal proteins   Alpha-fetoprotein (AFP) Hepatoma , Testicular cancer Carcinoembryonic antigen (CEA) Gastrointestinal cancers , Lung, ovarian cancers Secreted tumor antigens   CA 125 Ovarian cancers; Other epithelial cancers CA 19-9 Various carcinomas Prostate-specific antigen Prostate cancer β 2 microglobulin Multiple myeloma Hormones β subunit of chorionic gonadotropin Hydatidiform mole Choriocarcinoma ; Testicular cancers

31. IMMUNE RESPONSE AGAINST TUMOUR CELLS 32 Both humoral and cell-mediated immune responses are induced by tumour antigens that result in the destruction of the tumour cells. Cell-mediated response appears to play the major role: Cytotoxic T cell NK cell.

32. Cytotoxic T Cells 33 Number of tumours have been shown to induce tumor -specific T C cells that recognize tumour antigens presented by class I MHC on the tumour cells. Sensitized T-cells attack the foreign tumour cells and tend to limit its growth. T-cell subsets, cytotoxic T ( Tc ) cells play a significant role in tumour killing by means of lymphokines that they release.

33. Natural Killer (NK) Cells 34 Recognition of tumour cells by NK cells is not MHC restricted. NK cells can also kill the tumour cells without antibody. Direct lysis of tumour cells, NK cells also participate in antibody dependent cytotoxicity (ADCC). NK cells provide first line of defence against many tumours.

34. CANCER IMMUNOTHERAPY 35 Is the use of the immune system to treat cancer. Three main groups of immunotherapy are used to treat cancers: Checkpoint inhibitors Chimeric antigen receptor (CAR) T-cell therapy Antibody therapy Cytokines therapy Immunomodulators : boost up the immune system to treat cancer.

35. Checkpoint inhibitors 36 These drugs work by blocking checkpoint proteins from binding with their partner proteins. This will prevent the “off ” signal from being sent and thus allows the T-cell to kill cancer cells. Example: Ipilimumab which acts against a checkpoint proteins called CTLA-4 (cytotoxic T-lymphocyte- associated antigen 4)

36. Chimeric antigen receptor (CAR) T-cell therapy 37 It is a new form of immunotherapy. T-cells taken from patient’s blood are mixed with a special virus which makes the T-cells learn how to attach to tumour cells. This is done by inserting a gene for a special receptor called a chimeric antigen receptor (CAR) into the T-cells. These modified T-cells are called CAR-T cells. These CAR-T cells are given to the patient, they attach to tumour cells and kill the cancer. Example; Tisagenlecleucel for acute lymphoblastic leukemia (ALL) Axicabtageneciloleucel for large B cell lymphoma.

37. Monoclonal Antibodies 38 Monoclonal antibody ( mAb ) therapies - currently the most successful form of immunotherapy. Many mAbs are approved for treatments of a wide range of cancers

38. Monoclonal antibodies approved for treatment of cancers 39 Monoclonal antibodies Target Approved for treatment of cancers Alemtuzumab CD52 C hronic lymphocytic leukemia  (CLL) Bevacizumab Vascular endothelia growth factor Colorectal, lung and renal cancer Cetuximab Epidermal growth factor receptor Colorectal, the head and neck cancer Ipilimumab CTLA4 Metastatic  melanoma Rituximab CD20 CLL Non-Hodgkin lymphoma Tositumomab CD20 Trastuzumab ErbB2 Breast cancer

39. Cytokine Therapies 40 Regulate and coordinate the behavior of the immune system. Examples include: Interferon- α is used in the treatment of hairy-cell leukaemia , AIDS-related Kaposi's sarcoma, follicular lymphoma, chronic myeloid leukemia and malignant melanoma. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma.

40. Cancer Vaccine 41 Preventive cancer vaccines : Example - HPV and hepatitis B vaccine Prevent the emergence cervical and liver cancers respectively. Therapeutic cancer vaccines: Treat existing cancers. Research is ongoing - for preparation of such vaccines. Vaccines against some oncogenic viruses have proven extremely effective.

41. Oncolytic viruses 42 Oncolytic viruses are modified in a laboratory to infect and kill certain tumour cells. These virus are selectively replicate in cancer cells to destroy them. Example: Talimogene laherparepvec (T-VEC) is used to treat melanoma.

42. Thank You!!