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IMMUNOLOGY OF TRANSPLANT AND MALIGNANCY © Universities Press (India) Private Limited Universities Press IMMUNOLOGY OF TRANSPLANTATION • Result of disease or injury, an organ or tissue becomes irreparably damaged or organ congenitally defective or absent • TRANSPLANTATION or GRAFTING – Necessary for restoration of function © Universities Press (India) Private Limited Universities Press IMMUNOLOGY OF TRANSPLANTATION • Transplant or graft – Tissue or organ transplanted • Donor – Individual from whom the transplant is obtained • Recipient - Individual to whom transplant is applied © Universities Press (India) Private Limited Universities Press CLASSIFICATION OF TRANSPLANT • Based on organ or tissue transplanted kidney, heart, skin © Universities Press (India) Private Limited Universities Press CLASSIFICATION OF TRANSPLANT • Based on anatomical site of origin and site of its placement • Orthotopic - Grafts applied in anatomically ‘normal’ sites – as in skin grafts • Heterotopic – Grafts placed in anatomically ‘abnormal’ sites – as in thyroid tissue in subcutaneous pockets © Universities Press (India) Private Limited Universities Press CLASSIFICATION OF TRANSPLANT • Transplants – Fresh tissue and organs or stored ones, living or dead materials • Vital grafts – live graft – kidney, heart • Structural (static) grafts – non-living transplants like bone or artery © Universities Press (India) Private Limited Universities Press TYPES OF GRAFTS • Based on genetic relationship between the donor and the recipient • Autograft – Organ or tissue taken from an individual and grafted on him/herself © Universities Press (India) Private Limited Universities Press TYPES OF GRAFTS • Isograft – Graft taken from an individual and placed on another individual of the same genetic constitution Example: Grafts between identical twins © Universities Press (India) Private Limited Universities Press TYPES OF GRAFTS • Allograft (formerly homograft) - Grafts between two genetically non-identical members of the same species • Xenograft (formerly heterograft) – Graft between members of the same species © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • Skin graft from animal (such as rabbit) applied on genetically unrelated animal of the same species – graft appears to be accepted initially • Graft – vascularised – seems morphologically and functionally healthy – first 2-3 days © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • However by 4th day - inflammation evident – graft invaded by lymphocytes and macrophages • Blood vessels - occluded by thrombi, vascularity diminishes, graft undergoes ischemic necrosis © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • With extending necrosis - graft assumes a scab–like appearance, sloughs off – 10th day. • First set response (first set rejection or reaction) - Sequence of events, resulting in rejection © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION Allograft reaction © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • If in an animal that has rejected a graft by first set response, another graft from the same donor is applied, it is rejected in an accelerated fashion • Second set response – Accelerated allograft rejection © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION Allograft reaction © Universities Press (India) Private Limited Universities Press MECHANISM OF ALLOGRAFT REJECTION • Immunological basis of graft rejection – specificity of second set response • Accelerated rejection – if second graft from same donor as first • Application of skin graft from another donor- evokes only first set response © Universities Press (India) Private Limited Universities Press ADOPTIVE IMMUNITY • Allograft accepted if animal rendered immunologically tolerant • Adoptive immunisation - Transferring immunity by means of lymphoid cells © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY • Predominantly cell mediated First set response – T lymphocytes • Detected by – hemagglutination, lymphocytotoxicity, complement fixation, immunofluorescence © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY Second set response • Antibodies formed more rapidly and abundantly • White graft response – Graft applied to animal possessing specific antibodies in high titres - hyperacute rejection © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY • White graft response – Graft remains pale, rejected within hours - without even an attempt at vascularisation • Seen in human recipients of kidney transplants – who may possess pre-existing antibodies – due to prior transplantation, transfusion or malignancy © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY Immunological enhancement • Humoral antibodies may act in opposition to cell mediated immunity by inhibiting graft rejection • Kaliss – tumour transplants © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY Immunological enhancement • Recipient – pretreated with killed donor tissue – transplant applied - survives longer than in control animals • Enhancing effect – passively transferred by serum –humoral antibodies © Universities Press (India) Private Limited Universities Press TRANSPLANTATION IMMUNITY Immunological enhancement • Afferent inhibition – Antibodies combine with antigens released from the graft • Central inhibition - Antibodies combine with lymphoid cells - negative feedback • Efferent inhibition – Antibodies coat the surface of the cells in the graft © Universities Press (India) Private Limited Universities Press HISTOCOMPATIBILITY ANTIGENS Major Histocompatibility Complex (MHC) • Primary function – immune system – recognition and elimination of foreign cells and antigens that enter the body • Gorer -1930 - antigens responsible for allograft rejection – discovery of MHC © Universities Press (India) Private Limited Universities Press MHC – CLASSES OF PROTEINS • Class I proteins – Determine histocompatibility and acceptance or rejection of allograft • Class II proteins – Regulate immune response • Class III proteins – Include some components of the complement system © Universities Press (India) Private Limited Universities Press HISTOCOMPATIBILITY ANTIGENS • Immune response transplant - Antigens in grafted tissue - absent in recipient – hence foreign • If recipient possesses all the antigens present in the graft, no immune response and no graft rejection © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • First generation (F1) hybrids between two inbred strains – antigens representative of both the parent strains • Therefore accept grafts from either of the parental strains © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • If two parental strains have genotypes AA and BB • F1 hybrid – Genotype AB can accept tissues with genotype AA and BB • Transplantation in the reverse direction (from F1 to parent) will not succeed as strain AA will react against antigen B and strain BB will react against antigen A © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • Transplants between inbred strains of animals – successful – EXCEPTION – donor is male – recipient – female • Graft rejected – Grafted male tissue (XY) will have antigen determined by Y chromosome which is absent in female • Eichwald – Silmser effect – Unilateral sexlinked histoincompatibility © Universities Press (India) Private Limited Universities Press ALLOGRAFT REACTION • Transplantation or histocompatibility antigens – Antigens that participate in graft rejection • Major histocompatibility system – System of cell antigens that exerts a decisive influence on the fate of the allograft • Major histocompatibility system in humans is the human leucocyte antigen (HLA) © Universities Press (India) Private Limited Universities Press HISTOCOMPATIBILITY TESTING • Blood grouping – ABO blood group antigen • HLA compatibility – tested by – HLA typing – Tissue matching • HLA typing – Identifies the HLA antigens present on the surface of the leucocytes © Universities Press (India) Private Limited Universities Press METHODS OF HLA TYPING • Microcytotoxicity test • Molecular methods • Tissue matching © Universities Press (India) Private Limited Universities Press MICROCYTOTOXICITY TEST • Lymphocyte suspensions added to microwells of tissue typing trays predispensed with a panel of HLA typing sera • Incubated with complement • Cells carrying antigens corresponding to the HLA antiserum – killed by complement mediated membrane damage © Universities Press (India) Private Limited Universities Press MICROCYTOTOXICITY TEST • Detected by addition of eosin or trypan blue – stains only dead cells • Lymphocyte presumed to have HLA antigens – corresponding to the antisera that caused cell death – indicated by staining © Universities Press (India) Private Limited Universities Press MOLECULAR METHODS • Restriction fragment length polymorphism • Southern blotting • Polymerase chain reaction - using sequence specific primers © Universities Press (India) Private Limited Universities Press TISSUE MATCHING • Mixed lymphocyte reaction or culture (MLR or MLC) • T lymphocytes in culture, when exposed to HLA incompatible antigens – undergo blast transformation • Intensity of the reaction - Measure of the antigenic disparity between donor and recipient lymphocytes © Universities Press (India) Private Limited Universities Press IMMUNOSUPPRESSION • Immunosuppression inhibits – allograft rejection • Immunosuppressive drugs – steroids, azathioprine, cyclosporin A © Universities Press (India) Private Limited Universities Press PRIVILEDGED SITES • Sites at which allografts survive from immunological attack – Fetus – intrauterine allograft – Cartilage – impenetrable to immunocompetent cells – Brain – lymphatic drainage is absent – Corneal transplant – lack of vascularity at the site © Universities Press (India) Private Limited Universities Press GRAFT VERSUS HOST REACTION • Host versus graft – reaction of the host to grafted tissue • Graft versus host – graft mounts an immune response against antigens of the host © Universities Press (India) Private Limited Universities Press GRAFT VERSUS HOST REACTION • GVH occurs when the following conditions are present: – Graft contains immunocompetent cells – Recipient possess – transplantation antigens that are absent in the graft – Recipient must not reject the graft © Universities Press (India) Private Limited Universities Press GRAFT VERSUS HOST REACTION • Situations leading to GVH reaction: – Allograft in recipient in whom specific immunological tolerance has been induced – Adult lymphocytes injected into an immunologically deficient recipient – F1 hybrid receiving a transplant from any one parental strain © Universities Press (India) Private Limited Universities Press GVH CLINICAL FEATURES • Retardation of growth • Emaciation • Diarrhea • Hepatosplenomegaly • Lymphoid atrophy • Anemia • Terminating fatally • SYNDROME called runt disease © Universities Press (India) Private Limited Universities Press IMMUNOLOGY OF MALIGNANCY • Cell – malignant transformation – acquires – new surface antigens- loose some normal antigens • Tumour – antigenically different from normal host tissue • Tumour considered allograft – induce immune response © Universities Press (India) Private Limited Universities Press IMMUNOLOGY OF MALIGNANCY Clinical evidence of immune response in malignancy: • Spontaneous regression • Chemotherapy – cures • Overcome defence mechanisms • Cellular response • Immunodeficiency states © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY Spontaneous regression • Neuroblastoma and malignant melanoma • Recovery from malignancy – immune response © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY Chemotherapy - cures • Choriocarcinoma and Burkitt’s lymphoma cytotoxic drugs – complete cure • Hypernephroma and pulmonary metastasisremoval of primary tumour – regression of metastasis © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY Overcome defence mechanisms • Immune system is able to deal with malignant cells and only some of them overcome defence mechanisms and develop clinical cancer © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY Cellular response • Histology – lymphocytes, plasma cells and macrophages infiltrate tumours – cellular response – allograft reaction • Tumour showing cellular infiltration - better prognosis © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY Immunodeficiency states • Increased incidence of cancer, particularly lymphoreticular malignancies found in: – Congenital immunodeficiency states – AIDS – Patients undergoing chronic immunosuppressive therapy © Universities Press (India) Private Limited Universities Press TUMOUR ANTIGENS Tumour-specific antigens • Antigens present in malignant cells, absent in normal cells of the host • Induce immune response – when tumour transplanted in syngenic animals • Tumour–specific transplantation antigens (TSTA) – induce rejection of tumour transplants in immunised hosts © Universities Press (India) Private Limited Universities Press TUMOUR ANTIGENS Tumour-associated antigens • Oncofetal antigens: found in embryonic and malignant cells, but not in normal cells Example: Alphafetoprotein in hepatoma • Carcinoembryonic antigen in colonic carcinoma Differential antigens Example: Prostate specific antigen (PSA) in prostatic cancer; CA 125 in ovarian cancer © Universities Press (India) Private Limited Universities Press TUMOUR ANTIGENS Oncofetal antigen • Alphafetoprotein – alpha globulin - secreted by normal embryonic hepatocytes • Serum levels drop after birth, hardly detectable in adults • High levels – hepatic carcinoma – diagnostic values © Universities Press (India) Private Limited Universities Press TUMOUR ANTIGENS • Carcinoembryonic antigen – glycoprotein – serum of patient – carcinoma colon • Also appears in alcoholic cirrhosis • Diagnostic value limited © Universities Press (India) Private Limited Universities Press TUMOUR ANTIGENS Differential antigens • Prostate specific antigen (PSA): High in prostate cancer • CA 125: Cancer/carbohydrate antigen 125 diagnostic and prognostic marker for ovarian cancer © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY • Humoral and cellular immune response • Anti TSTA antibodies – demonstrated by indirect membrane electrophoresis © Universities Press (India) Private Limited Universities Press IMMUNE RESPONSE IN MALIGNANCY • Delayed hypersensitivity – Detected by skin testing with tumour cell extracts • CMI – Demonstrated by stimulation of DNA synthesis and lymphokine production • CMI – Host defence against malignancy © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Lewis Thomas – 1950 • Primary function of CMI – ‘seek and destroy’ malignant cells • Inefficiency of the surveillance mechanism – either as a result of: – Ageing – Congenital or acquired immunodeficiency, leading to increased incidence of cancer © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Mechanism – lapse in surveillance – possibly due to: – Very fast rate of proliferation of malignant cells – Cells may be able to ‘sneak through’ before development of effective immune response – A certain mass of cells may be beyond the power of immunological attack © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE Mechanism • Circulating tumour antigens: May act as ‘smokescreen’ – coating the lymphoid cells and preventing them from acting on the tumour cells © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Tumour antigens on malignant cells may be inaccessible to sensitised cells being covered by some antigenically neutral substance © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Humoral antibodies – cause immunological enhancement • Blocking activity – circulating antigen, antibody or antigen-antibody complexes © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Tumour – low immunogenicity or forms cytokines like transforming growth factor β (TGF β ) which suppress CMI © Universities Press (India) Private Limited Universities Press IMMUNOLOGICAL SURVEILLANCE • Tumour cells express low levels of class I MHC molecules and hence may not be recognised by CD8 and CTLs for destruction © Universities Press (India) Private Limited Universities Press IMMUNOTHERAPY OF CANCER Different approaches • Passive immunotherapy • Specific active immunotherapy • Non-specific active immunotherapy • Specific adoptive immunotherapy © Universities Press (India) Private Limited Universities Press PASSIVE IMMUNOTHERAPY Earliest method • Serotherapy – antisera that possess ‘deblocking’ activity in vitro - cause regression of tumours – by neutralising the circulating tumour antigens and permit the sensitised lymphocytes to act on tumour cells © Universities Press (India) Private Limited Universities Press SPECIFIC ACTIVE IMMUNOTHERAPY • Injection of tumour cell ‘vaccines’ • Purified tumour cell membrane antigen and tumour cells treated with neuraminidase to increase their immunogenic potential © Universities Press (India) Private Limited Universities Press NON–SPECIFIC ACTIVE IMMUNOTHERAPY • Uses BCG and non-living Corynebacterium parvum • Mathe – reported good results in acute leukemia - following combined treatment with BCG and allogeneic or autochthonous leukemia blast cells © Universities Press (India) Private Limited Universities Press NON-SPECIFIC ACTIVE IMMUNOTHERAPY • Intralesional BCG in malignant melanomacomplete remission • Also used against intradermal recurrence of breast cancer following mastectomy • Dinitrobenzene – treatment of squamous and basal cell carcinoma of the skin © Universities Press (India) Private Limited Universities Press NON–SPECIFIC ACTIVE IMMUNOTHERAPY • Glucan (a pyran copolymer) and levamisole (antihelminthic) - stimulate CMI and macrophage function • Interferons – treatment of leukemias © Universities Press (India) Private Limited Universities Press SPECIFIC ADOPTIVE IMMUNOTHERAPY • Lymphocytes, transfer factor and ‘immune RNA’ • Donor - Person cured of their neoplasm, OR specifically immunised against patient’s tumour © Universities Press (India) Private Limited Universities Press SPECIFIC ADOPTIVE IMMUNOTHERAPY • Lymphokine activated killer (LAK) cells obtained by treatment of the natural killer cells with interleukin 2 – useful for treatment of renal carcinomas © Universities Press (India) Private Limited Universities Press IMMUNOTHERAPY • Immunotherapy is ineffective in the presence of large mass of tumour cells • Important role in getting rid of residual malignant cells after gross tumour is removed © Universities Press (India) Private Limited Universities Press THERAPY • BEST RESULTS in the treatment of cancer – integrated approach – combining surgery, radiotherapy, chemotherapy and immunotherapy © Universities Press (India) Private Limited Universities Press
