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Transplantation and tumor immunology


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Transplantation and tumor immunology

  1. 1. Transplantation Immunology <ul><li>The immune response has evolved as a way of discriminating between self and nonself </li></ul><ul><li>Once foreignness has been established, immune response proceeds toward its ultimate goal of destroying the foreign material </li></ul><ul><ul><li>Be it a microorganism or its product, a substance present in the environment, or a tumor cell </li></ul></ul>
  2. 2. Transplantation Immunology, cont. <ul><li>Transplantation </li></ul><ul><li>Transfer of tissue or organ from one individual to another whereas transfusion refers to transfer of blood from one individual to another </li></ul><ul><ul><li>Antibodies are responsible for transfusion reactions; </li></ul></ul><ul><ul><li>Rejection of transplanted tissue is mediated predominantly by T cells </li></ul></ul>
  3. 3. Transplantation Immunology, cont. <ul><li>Gradations in relationships of transplantation from donor to recipient are: </li></ul><ul><li>Autograft </li></ul><ul><li>A graft or transplant from one area to another on the same individual </li></ul><ul><ul><li>Transplantation of normal skin from one area of an individual to a burned area of the same individual </li></ul></ul><ul><li>Graft is recognized as autologous (self) </li></ul>
  4. 4. Transplantation Immunology, cont. <ul><li>No immune response is induced against it </li></ul><ul><li>Barring technical difficulties in the transplantation, the graft will survive or take in its new location </li></ul><ul><li>Isograft or Syngraft </li></ul><ul><li>Graft or transplantation of cells, tissue or organ from one individual to another individual who is syngeneic (genetically identical) to the donor </li></ul><ul><ul><li>Transplantation of a kidney from one identical (homozygotic) twin to the other </li></ul></ul>
  5. 5. Transplantation Immunology, cont. <ul><li>The recipient who is genetically identical to the donor recognizes the donor’s tissue as self </li></ul><ul><li>And does not mount an immune response against it </li></ul><ul><li>The 2 individuals i.e. donor and recipient are histocompatible </li></ul><ul><li>Allograft </li></ul><ul><li>Graft or transplant from one individual to a genetically dissimilar individual of the same species </li></ul>
  6. 6. Transplantation Immunology, cont. <ul><li>Since all individuals of a given outbreed species, except monozygotic twins, are allogeneic (genetically dissimilar), regardless of how closely they may be related </li></ul><ul><li>Graft is recognized by recipient as foreign and is immunologically rejected </li></ul><ul><li>The donor and recipient, in this case, are nonhistocompatible or histoincompatible </li></ul>
  7. 7. Transplantation Immunology, cont. <ul><li>Xenograft </li></ul><ul><li>Graft between a donor and a recipient from different species </li></ul><ul><li>Transplant is recognized as foreign and immune response mounted against it will destroy or reject graft </li></ul><ul><li>Donor and recipient are again described as histoincompatible </li></ul>
  8. 8. Transplantation Immunology, cont. <ul><li>Role of Immune Response in Allograft Rejection </li></ul><ul><li>Mouse skin with black hair transplanted onto the back of a white-haired mouse (between allogeneic donor and recipient) appears normal for 1 or 2 wks </li></ul><ul><li>After approx. 2 wks, transplant begins to be rejected </li></ul><ul><li>Is completely sloughed off within a few days, process is called first-set rejection </li></ul>
  9. 9. Transplantation Immunology, cont. <ul><li>If after this rejection, recipient is transplanted with another piece of skin from same initial donor, process of rejection is accelerated  second-set rejection </li></ul><ul><li>The graft is sloughed quicker, within about a week of second transplant </li></ul><ul><li>In contrast, a piece of skin from a genetically different strain grafted onto this same mouse is rejected with first-set kinetics </li></ul>
  10. 10. Transplantation Immunology, cont. <ul><li>Thus, second-set rejection is an expression of specific immunologic memory for antigens expressed by the graft </li></ul><ul><li>Participation of T cells in the rejection response can be shown by transferring T cells from an individual sensitized to an allograft into a normal syngeneic recipient </li></ul><ul><li>If the second recipient is transplanted with same allograft that was used on the original T-cell donor, a second-set rejection ensues </li></ul>
  11. 11. Transplantation Immunology, cont. <ul><li>Many other lines of evidence establish immunologic nature of graft rejection </li></ul><ul><li>Histologic examination of the site of rejection reveals lymphocytic and monocytic cellular infiltration reminiscent of delayed-type hypersensitivity reaction </li></ul><ul><ul><li>Both CD4+ and CD8+ cells are present at the site </li></ul></ul>
  12. 12. Transplantation Immunology, cont. <ul><li>Individuals that lack T lymphocytes such as athymic or nude, mice or humans with DiGeorge syndrome) do not reject allografts or xenografts </li></ul><ul><li>Process of rejection slows down considerably or does not occur at all in immunosupressed individuals </li></ul><ul><li>Has been conclusively demonstrated that specific T cells and circulating antibodies are induced to an allograft or a xenograft </li></ul>
  13. 13. Transplantation Immunology, cont. <ul><li>However, T cells constitute major immunologic component responsible for rejection of allograft tissues </li></ul><ul><li>Certain antibodies that are not effective in the process of graft rejection compete with T cells for transplantation antigens, thereby blocking the process of rejection mediated by T cells and enhancing the survival of graft  enhancing antibodies </li></ul><ul><ul><li>Relevance of this phenomenon still unclear </li></ul></ul>
  14. 14. Transplantation Immunology, cont. <ul><li>Clinical Characteristics of Allograft Rejection </li></ul><ul><li>Fall into 3 major categories: </li></ul><ul><ul><li>Hyperacute rejection </li></ul></ul><ul><ul><li>Acute rejection </li></ul></ul><ul><ul><li>Chronic rejection </li></ul></ul>
  15. 15. Transplantation Immunology, cont. <ul><li>Hyperacute rejection </li></ul><ul><li>Occurs within a few minutes to a few hours of transplantation </li></ul><ul><li>Result of destruction of transplant by preformed antibodies such as in ABO blood group incompatibility </li></ul><ul><li>No transplantation will be performed, or preformed antibodies to the graft, synthesized as a result of previous transplantations, blood transfusions, or pregnancies </li></ul>
  16. 16. Transplantation Immunology, cont. <ul><li>These antibodies activate complement system followed by platelet activation and deposition causing swelling and interstitial hemorrhage in the transplanted tissue, which decrease the flow of blood thro tissue </li></ul><ul><li>Thrombosis with endothelial injury fibrinoid necrosis are often seen </li></ul><ul><li>Recipient may have fever, leukocytosis and produce little or no urine </li></ul><ul><ul><li>Urine may contain various cellular elements such as erythrocytes </li></ul></ul>
  17. 17. Transplantation Immunology, cont. <ul><li>Cell mediated immunity is not involved at all </li></ul><ul><li>At present there is no therapy for successful prevention or termination of hyperacute rejection </li></ul><ul><li>Acute Rejection </li></ul><ul><li>Seen in a recipient who has not previously been sensitized to transplant </li></ul><ul><li>Cell mediated immunity mediated by T cells is the primary cause of acute rejection </li></ul>
  18. 18. Transplantation Immunology, cont. <ul><li>Common type of rejection experienced by individuals for whom transplanted tissue is a mismatch </li></ul><ul><li>Or who receive an allograft and insufficient immunosuppressive treatment to prevent rejection </li></ul><ul><li>Reaction may begin a few days after transplantation of a kidney, with a complete loss of kidney function within 10-14 days </li></ul><ul><li>Accompanied by a rapid decrease in renal function </li></ul>
  19. 19. Transplantation Immunology, cont. <ul><li>Enlargement and tenderness of grafted kidney, a rise in serum creatinine levels, a fall in urine output, decreased renal blood flow are characteristic </li></ul><ul><li>Histologically, CMI manifested by intense filtration of lymphocytes and macrophages, is taking place at rejection site </li></ul><ul><li>May be reduced by immunosuppressive therapy such as antilymphocytic serum, corticosteroids, or other drugs </li></ul>
  20. 20. Transplantation Immunology, cont. <ul><li>Chronic rejection </li></ul><ul><li>Caused by both antibody and cell-mediated immunity occurs in allograft transplantation months after transplanted tissue has assumed its normal function </li></ul><ul><li>In kidney transplantation, is characterized by slow, progressive renal failure </li></ul><ul><li>Histologically, is accompanied by proliferative inflammatory lesions of small arteries, thickening of glomerular basement membrane and interstitial fibrosis </li></ul>
  21. 21. Transplantation Immunology, cont. <ul><li>Because damage caused by immune injury has already taken place, immunosuppressive therapy at this point is useless </li></ul><ul><ul><li>Little can be done to save the graft </li></ul></ul><ul><li>Rate, extent and underlying mechanisms of rejection may vary depending on the transplanted tissue and site of transplanted graft </li></ul>
  22. 22. Transplantation Immunology, cont. <ul><li>Recipient circulation, lymphatic drainage, expression of strong antigens on the graft and several other factors determine rejection rate </li></ul><ul><li>Bone marrow and skin grafts are very sensitive to rejection compared to heart, kidney and liver </li></ul>
  23. 23. Transplantation Immunology, cont. <ul><li>Prolongation of Allografts </li></ul><ul><li>Several measures are taken during transplantation that are aimed at prolonging graft survival; mostly suppress entire immune response in a non-antigen-specific way </li></ul><ul><li>Anti-inflammatory agents – corticosteroids such as prednisolone </li></ul><ul><li>Antimetabolites – azathioprine, mercaptopurine, chlorambucil and cyclophosphamide </li></ul>
  24. 24. Transplantation Immunology, cont. <ul><li>Cytotoxic and blocking agents – antilymphocytic serum (ALS), antilymphocytic globulins (ALGs), steroids, alkylating agents, X-rays and antibiotics such as actinomycin D </li></ul><ul><li>Cyclosporine and FK 506 </li></ul><ul><li>Total lymphoid irradiation </li></ul>
  25. 25. Transplantation Immunology, cont. <ul><li>Graft-versus-host (GVH) reactions </li></ul><ul><li>Transplantation of immunocompetent lymphocytes from a donor to a genetically different recipient can result in a reaction mounted by the grafted lymphocytes against recipient’s tissue </li></ul><ul><li>Is particularly important in cases where immunocompetent lymphoid cells are transplanted into individuals who are immunologically incompetent, therefore can not reject transplanted cells </li></ul>
  26. 26. Transplantation Immunology, cont. <ul><li>GVH disease may occur in bone marrow transplant recipients even if the donor and recipient are perfectly HLA-matched </li></ul><ul><li>This is probably due to minor, non-HLA-coded, transplantation antigens recognized by donor T cells </li></ul><ul><li>In humans, may produce splenomegally, enlarged liver and lymph nodes, diarrhoea, anemia, weight loss and other disorders in which underlying causes are inflammation and destruction of tissue </li></ul>
  27. 27. Transplantation Immunology, cont. <ul><li>Initiated by the transferred T lymphocytes from donor, which recognize recipient’s transplantation antigens as foreign </li></ul><ul><li>Donor T cells thus become activated as in an allograft response </li></ul><ul><li>In GVH disease, however, most of inflammatory cells that participate in the reaction and that are mainly responsible for destruction of tissue, are host cells recruited to site of reaction by lymphokines released by donor’s lymphocytes </li></ul>
  28. 28. Tumor Immunology <ul><li>Existence of an immune response against a tumor is based on changes in the surface components of malignant cell that do not occur in its normal counterpart </li></ul><ul><li>And that give rise to structures that are antigenic </li></ul><ul><li>Goals </li></ul><ul><li>To elucidate the immunologic relationship between the host and the tumor and </li></ul><ul><li>To utilize immune response to tumors for purpose of diagnosis, prophylaxis and therapy </li></ul>
  29. 29. Tumor Immunology, cont. <ul><li>Tumor Antigens </li></ul><ul><li>Some antigens on the surface of malignant cells may consist of structures that are unique to cancerous cells and are not present on their normal counterparts  tumor-specific transplantation antigens (TSTAs) or simply tumor-specific antigens (TSAs) </li></ul><ul><li>Other tumor antigens may represent structures that are common to both malignant and normal cells but are masked on the normal cells and become unmasked on malignant cells </li></ul>
  30. 30. Tumor Immunology, cont. <ul><li>Still other antigens on tumor cells represent structures that are qualitatively not different from those found on normal cells but that are over expressed – present at significantly increased numbers on the cancer cell as products of cellular oncogenes  tumor-associated antigens (TAAs) </li></ul><ul><ul><li>High levels of a growth factor receptor due to increased expression of the neu oncogene products found in a number of human breast cells, and elevated ras oncogene products present on some human prostate cancer cells </li></ul></ul>
  31. 31. Tumor Immunology, cont. <ul><li>Still other antigens on malignant cells represent structures that are present on fetal or embryonic cells but disappear from normal adult cells  oncofetal or oncodevelopmental antigens </li></ul><ul><li>Classification of tumor antigens </li></ul><ul><li>May be classified into 4 major categories </li></ul><ul><ul><li>Differ in both factors that induce malignancy and immunochemical properties of tumor antigens </li></ul></ul>
  32. 32. Tumor Immunology, cont. <ul><li>Antigens of tumors induced by chemical or physical Carcinogens </li></ul><ul><li>Exhibits a unique antigen specificity </li></ul><ul><li>Cells of a given tumor, arising from a single transformed cell, all share common antigens, but different tumors, even if induced by the same carcinogen, are antigenically distinct from one another </li></ul>
  33. 33. Tumor Immunology, cont. <ul><li>If the chemical carcinogen methylcholanthrene is applied in identical manner to skin of two genetically identical animals, or on two similar sites on the same individual, cells of developing tumors (sarcomas) will exhibit antigens unique to each tumor, with no immunologic cross-reactivity between tumors </li></ul><ul><li>There is little or no cross-reactivity between physically induced tumors, such as those induced by UV light or by X irradiation </li></ul>
  34. 34. Tumor Immunology, cont. <ul><li>Absence of cross-reactivity is probably due to random mutations induced by chemical or physical carcinogens leading to a large array of different antigens </li></ul><ul><li>Since most human and animal tumors are attributed to chemical and physical environmental factors such as radiation, smoke, and tar, these tumors, which lack immunologic cross-reactivity, are unfortunately not expected to be amenable to diagnosis, prophylaxis or therapy by immunologic means </li></ul>
  35. 35. Tumor Immunology, cont. <ul><li>Antigens of virally induced tumors </li></ul><ul><li>Animal studies have shown that tumors induced by DNA or RNA oncogenic virus exhibit extensive immunologic cross-reactivity </li></ul><ul><li>Because any particular oncogenic virus induces expression of same antigens in a tumor, regardless of tissue origin or animal species </li></ul>
  36. 36. Tumor Immunology, cont. <ul><li>DNA viruses such as polyoma, SV40 and Shope papilloma virus induce tumors that exhibit extensive cross-reactivity within each virus group </li></ul><ul><li>Many leukemogenic viruses such as Raucher leukemia virus, induce formation of tumors that exhibit cross-reactivity not only within each virus group but also between some groups </li></ul>
  37. 37. Tumor Immunology, cont. <ul><li>There is considerable circumstantial evidence to suggest that several human cancers such as Burkitt’s lymphoma, nasopharyngeal carcinoma, T-cell leukemia, and hepatocellular carcinoma are caused by viruses </li></ul><ul><li>Cross-reactivity is well established for cell surface antigens of Burkitt’s lymphomas or of neuroblastomas from different patients </li></ul>
  38. 38. Tumor Immunology, cont. <ul><li>Colon carcinoma cells obtained from different patients also exhibit immunologic cross-reactivity, as do melanoma cells from different patients </li></ul><ul><li>Some antigens of virally induced tumors are encoded by the virus, but they are distinct from virion antigens  tumor-associated antigens (TAA) </li></ul><ul><li>Occasionally, virally induced tumors may express oncofetal antigens, encoded by the host genome </li></ul>
  39. 39. Tumor Immunology, cont. <ul><li>Oncodevelopmental tumor antigens </li></ul><ul><li>Many tumors express on their surface, or secrete into blood, products that are normally present during embryonic and fetal development, but that are either absent or present at very low levels in normal adult tissue </li></ul><ul><li>These structures are not immunogenic in the autochthonous (native or original) host </li></ul><ul><li>Their presence can be detected by antisera prepared against them in allogeneic or xenogeneic animals </li></ul>
  40. 40. Tumor Immunology, cont. <ul><li>E.g. Carcinoembryonic antigen (CEA) found primarily in serum of patients with cancers of gastrointestinal tract esp. cancer of colon </li></ul><ul><ul><li>Elevated levels have also been detected in the circulation of patients with some types of lung cancer, pancreatic cancer and some types of breast and stomach cancer </li></ul></ul><ul><ul><li>However, elevated levels of CEA also detected in patients with emphysema, ulcerative colitis, and pancreatitis as well as in the sera of alcoholics and heavy smokers </li></ul></ul>
  41. 41. Tumor Immunology, cont. <ul><li> -fetoprotein (AFP), which is normally present at high concentrations in fetal and maternal serum but absent from serum of normal individuals </li></ul><ul><li>Rapidly secreted by cells of a variety of cancers and is found particularly in patients with hepatomas and testicular teratocarcinomas </li></ul>
  42. 42. Tumor Immunology, cont. <ul><li>Association of oncodevelopmental antigens with a wide variety of tumor types strongly suggests that derepression of normal genes that are usually repressed in the normal adult individual is a concomitant malignancy </li></ul><ul><li>Antigens of spontaneous tumors </li></ul><ul><li>Spontaneous tumors are induced by unknown causes </li></ul>
  43. 43. Tumor Immunology, cont. <ul><li>With recent advent of sensitive detection techniques, antibodies to autochthonous tumors have been found in patients with some tumors, most notably malignant melanoma </li></ul><ul><li>In some cases, antigens exhibit immunologic cross-reactivity, in other cases they do not </li></ul><ul><li>Thus, antigens of spontaneous tumors seem to resemble those of chemically or virally induced tumors with respect to immunologic specificity </li></ul>
  44. 44. Tumor Immunology, cont. <ul><li>Immune response to tumors: humoral and cellular effector immune mechanisms in tumor cell destruction </li></ul><ul><li>Humoral mechanisms </li></ul><ul><li>Lysis by antibody and complement </li></ul><ul><li>Antibody-mediated and complement mediated opsonization </li></ul><ul><li>Antibody-mediated loss of tumor cell adhesion </li></ul>
  45. 45. Tumor Immunology, cont. <ul><li>Cellular mechanisms </li></ul><ul><li>Destruction by cytotoxic cells </li></ul><ul><li>Antibody-dependent, cell-mediated cytotoxicity (ADCC) </li></ul><ul><li>Destruction by activated macrophages </li></ul><ul><li>Destruction by natural killer (NK) cells </li></ul>
  46. 46. Tumor Immunology, cont. <ul><li>Role of immune response in the relationship between host and tumor </li></ul><ul><li>Tumors in immunosuppressed individuals </li></ul><ul><li>Tumors occur more frequently in immunosuppressed individuals than in their normal counterparts </li></ul><ul><li>Such tumors are predominantly but not exclusively lymphoproliferative malignancies </li></ul>
  47. 47. Tumor Immunology, cont. <ul><li>Tumors in the immunocompetent host </li></ul><ul><li>Involvement of immune response in the host-tumor relationship is suggested by correlation between appearance of various immunologic effector mechanisms and state of resistance to transplanted tumors in experimental animals </li></ul><ul><li>There is a correlation between appearance of immune components at the site of tumor and regression of tumors in animals and humans </li></ul>
  48. 48. Tumor Immunology, cont. <ul><li>Concomitant immunity is expressed by host’s ability to reject newly arising or transplanted tumors of same type, despite progression of primary tumor </li></ul><ul><li>Immune surveillance </li></ul><ul><li>Propounded by Thomas in 1950 and expanded by Burnet later </li></ul><ul><li>Theory remains controversial and unproven </li></ul>
  49. 49. Tumor Immunology, cont. <ul><li>Limitations of effectiveness of immune response against tumors </li></ul><ul><li>Tumor resides in immunologically privileged site </li></ul><ul><li>Antigenic modulation of tumor antigens </li></ul><ul><li>Presence of enhancing or blocking factors </li></ul><ul><li>Suppressor T lymphocytes </li></ul><ul><li>Immune suppression by tumor cell products </li></ul><ul><li>Excessive tumor mass </li></ul>
  50. 50. Tumor Immunology, cont. <ul><li>Immunodiagnosis </li></ul><ul><li>May be performed to achieve two separate goals </li></ul><ul><ul><li>Immunological detection of antigens specific to tumor cells and </li></ul></ul><ul><ul><li>Assessment of host’s immune response to tumor </li></ul></ul>
  51. 51. Tumor Immunology, cont. <ul><li>Detection of tumor cells and their products by immunological means </li></ul><ul><li>Myeloma and Bence-Jones proteins e.g. plasma cell tumor </li></ul><ul><li>AFP e.g. liver cancer </li></ul><ul><li>CEA e.g. gastrointestinal cancers </li></ul><ul><li>Prostate-specific antigen (PSA) </li></ul><ul><li>Immunological detection of other tumor cell markers e.g. enzymes and hormones </li></ul>
  52. 52. Tumor Immunology, cont. <ul><li>Detection of tumor-specific antigens in the circulation or by immunoimaging </li></ul><ul><li>Detection of anti-tumor immune response </li></ul><ul><li>Anti-tumor antibodies </li></ul><ul><li>Anti-tumor cell-mediated immunity </li></ul><ul><li>Tumor immunoprophylaxis </li></ul><ul><li>Immunization against tumor itself requires that tumor possesses specific antigens and that these antigens cross-react immunologically with any prepared vaccine </li></ul>
  53. 53. Tumor Immunology, cont. <ul><li>Efficacy of immunoprophylaxis for protection of humans and animals against spontaneous tumors has not been sufficiently evaluated </li></ul><ul><li>Immunotherapy of tumors </li></ul><ul><li>Vaccination and adjuvant therapy </li></ul><ul><li>Cytokine therapy e.g. interferon  ,  ,  , IL-2, IL-4, IL-5, IL-12, TNF, lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs) </li></ul>
  54. 54. Tumor Immunology, cont. <ul><li>Anti-idiotype antibody therapy </li></ul><ul><ul><li>Dramatic regression have recently been reported in several lymphoma patients </li></ul></ul><ul><li>Immunotoxin therapy </li></ul><ul><ul><li>Toxins such as ricin, or radioactive isotopes attached to tumor-specific antibodies are delivered specifically to tumor cells for direct killing </li></ul></ul><ul><ul><li>Extent to which these immunotoxins will prove effective in the treatment of cancer remains to be established </li></ul></ul>