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Immunology of tanslanatation and malignancy

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Immunology of tanslanatation and malignancy

  1. 1. Immunology of Transplantation ad Malignancy Dr. Pendru Raghunath Reddy
  2. 2. Definition  Transplantation refers to the act of transferring cells, tissues or organs from one site to another  The tissue or organ trasplanted is known as the transplant or graft  The individual from whom the transplant is obtained is known as the donor and the individual to whom it is applied, the recipient or host
  3. 3. Can you imagine?
  4. 4. Applications of allografting transplantation
  5. 5. Allograft reaction  Rejection of the graft by the recipient is called the allograft reaction First set reponse  When a skin graft from an animal is applied on a genetically unrelated animal of the same species, the graft appears to be accepted initially  The graft is vascularized and seems morphologically and functionally healthy during the first two or three days  By about the fourth day, inflammation becomes evident
  6. 6.  The graft assumes a scab-like appearance with extending necrosis and sloughs off by the the tenth day Second set reponse  When a second allograft from the same donor is applied on a sensitised recipient, it will be rejected in an accelerated fashion  Necrosis sets in early and the graft sloughs off by the sixth day  Antibodies play a dominant role along with cell mediated immunity
  7. 7. First- and second-set allograft rejection Figure 16.1
  8. 8. For matching donor and recipient for transplantation following procedures are undertaken 1. ABO grouping 2. Tissue typing (detection of MHC antigens) (Microcytotoxicity test, Mixed lymphocytes culture (MLC) and Molecular methods)
  9. 9. Prevention of graft rejection 1. Immunosupression 2. Transplantation in anatomically protected (privilieged) sites  There are certain privileged sites where allografts are permitted to survive Examples: Cornea, Brain, Cartilage, Pancreatic islet cells
  10. 10. Fetus as allograft  The fetus can be considered an intrauterine allograft as it contains antigens which are foreign to the mother  The reason why the fetus is exempted from rejection is not clear, though many explanations have been offered 1. The palcenta acts as an immunological barrier 2. Mucoproteins 3. Blocking antibodies 4. MHC antigens 5. Alpha fetoprotein 6. β1- glycoprotein
  11. 11. Graft-Versus Host (GVH) reaction  Graft rejection is generally due to the reaction of the host to grafted tissue (host-versus-graft response)  Contrary to that, the graft may mount an immune response against the antigens of the host, this is known as “graft-versus-host reaction”  The GVH reaction occurs when the following conditions are present 1. The graft contains immunocompetent T cells 2. The recipient possesses HLA antigens that are absent in the graft 3. The recipient must not reject the graft
  12. 12.  The GVH reactions are predominantly cell mediated  GVH is a major complication of bone marrow transplantation and affects 50 to 70% of bone marrow transplant patients  Donor T cells recognise alloantigens on the host cells  The activation and proliferation of these T cells and the subsequent production of cytokines generate inflammatory reactions in the skin, gastrointestinal tract and liver
  13. 13.  The clinical manifestations of GVH reaction consists of splenomegaly, fever, rash, anaemia, weight loss and sometimes death  The clinical manifestations of GVH reaction in animals are retardation of growth, emaciation, diarrhea, hepatosplenomegaly, lymphoid atrophy and anaemia,terminating fatally (runting disease)
  14. 14. Tumour immunity  When a cell undergoes malignant transformation, it expresses new surface antigens and may also lose some normal antigens  The tumour associated antigens are immunologically distinct from normal tissue antigens  Therefore, tumour can be considered as an allograft and is expected to induce an immune response
  15. 15. Normal Cell Growth Control of cell growth Growth-promoting Proto-oncogenes Growth-restricting Tumor-suppressor genes
  16. 16. Molecular Basis of Cancer Uncontrolled cell growth Proto-oncogenes Tumor-suppressor genes Mutations Radiation Chemical (Carcinogen) Virus
  17. 17. Etiology of tumor 1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene 2) Viral: - Human papilloma, herpes type 2, HBV, EBV (DNA) - Human T-cell leuckemia virus (RNA) 3) Chemical: - Poly cyclic hydrocarbons cause sarcomas - Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma 4) Radiological: Ultraviolet & ionizing irradiation 5) Spontaneous: failure in the cellular growth control
  18. 18. Tumour antigens Major Histocompatability Complex antigens Tumor-specific Antigens TSTA (TSAs) Tumor-associated Antigens TATA (TAAs) TSTA: unique to a tumor Play an important role in tumor rejection. TATA: shared by normal and tumor cells Tumor-associated developmental Ag (TADA) Tumor-associated viral Ag (TAVA)
  19. 19. Tumour specific antigens (TSAs or TSTAs)  Unique to tumour cells and do not occur on normal cells in the body  TSAs or TSTAs have been identified on tumours induced with chemical or physical carcinogens and on some virally induced tumours  In chemically induced tumors, these antigens are tumour specific  Different tumours possess different antigens, even if they are induced by the same carcinogen  In contrast, the TSAs of virus induced tumours are virus specific
  20. 20. Tumour associated antigens (TAA or TATAs)  These are present on tumour cells and also on some normal cells  However, they are expressed at extremely low levels on normal cells but are expressed at much higher levels on tumour cells  They fall into three categories 1. Tumour associated carbohydrate antigens (TACAs) (Mucin-associated antigen detected in pancreatic and breast cancers) 2. Oncofetal antigens alphafetoprotein in hepatoma, carcinoembryonic antigen (CEA) in colonic cancer) 3. Differentiation antigens (PSA in prostatic cancer)
  21. 21. Immune response in malignancy  Tumour antigens can induce both humoral and cell mediated immune responses that result in the destruction of the tumour cells  The immune response to tumour includes CTL-mediated lysis, NK-cell activity, macrophage-mediated tumour destruction and destruction mediated by ADCC
  22. 22. Natural Killer Cells • NK Make up 5-10% of circulating lymphocytes – Major producers of IFN – Through IFN they influence innate immunity (M) – They also influence adaptive immunity by favoring TH1 – Eliminate viruses and tumor cells • Early responders to viral Infections – IFN and IFN stimulates NK activity – IFN production induces M to make IL-12 – IL-12 results in more IFN pushing towards TH1 – TH1 through IL-2 Induces CTL activation
  23. 23. • NK eliminate target cells same way as CTLs – Through perforin/granzyme and FasL/Fas • However they are different from CTLs – No Ag specific TCR – No CD3 – No MHC restriction – No memory, same intensity regardless of repeated exposure
  24. 24. Antibody Dependent Cell Mediated Cytotoxicity (ADCC) • Cells capable of cytotoxicity express Fc receptors • Antibody binds to target Cell, cytotoxic cells bind Fc portion of antibody • Antibody provides the specificity • Examples of cells capable of ADCC – M, NK, Neutrophils, eosinophils • Killing of target is accomplished – Through perforin, granzyme (NK, Eosinophils) – TNF (M, NK) – Lytic enzymes (M, Neutrophils, Eosinophils, NK)
  25. 25. Immunosurveillance  It is believed that malignant cells arise by mutation of somatic cells  The immune system keeps a consant vigilance on these malignant mutation of somatic cells and destroy them on the spot  The development of tumours represents an escape from this surveillance
  26. 26. The mechanisms of such escape are not clear but various possibilities have been suggested 1. Weak immunogenicity 2. Modulation of surface antigens 3. Masking tumour antigens 4. Supression of CMI 5. Fast rate of proliferation of malignant cells 6. Production of blocking antiodies 7. Low levels of HLA class I molecules
  27. 27. 34 Escape from immunosurveillance Lack of neo-antigens
  28. 28. 35 Escape from immunosurveillance Lack of class I MHC
  29. 29. 36 Escape from immunosurveillance Tumors secrete immuno-suppressive molecules
  30. 30. 37 Escape from immunosurveillance Production of blocking antibodies
  31. 31. Immunotherapy of cancer Different approaches have been attempted in the immunotherapy of cancer 1. Active a) Nonspecific b) Specific 2. Passive a) Nonspecific b) Specific c) Combined
  32. 32. Nonspecific active immunotherapy Biological response modifiers (BRMs) are used to enhance immune responses to tumours and fall into four major groups 1. Bacterial products (BCG, nonliving Corynebacterium parvum) 2. Synthetic molecules (Glucan, levamisole) 3. Cytokines 4. Hormones
  33. 33. Specific active immunotherapy Specific active immunotherapy includes therapeutic vaccines of tumour cells, cell extracts, purified or recombinant antigens, peptides, heat shock proteins, or DNA antigen-pulsed dendritic cells Passive immunotherapy Passive immunotherapy may be 1. Nonspecific (LAK cells) 2. Specific (antibodies alone or coupled to drugs, prodrugs, toxins or radioisotope, bispecific antibodies T cells) 3. Combined (LAK cells and bispecific antibody)

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