Transplantation And Malignancy

Immunology TRANSPLANTATION AND MALIGNANCY Classification of grafts:

Fresh Or

May be living or dead material

Cadaveric

Types of Grafts

Based on organ: Liver Kidney Heart Skin

Based on anatomical site: Orthotopic (at normal site) Heterotropic (not at normal site)

Genetic Classification: Autograft Allograft Isograft Xenograft

Genetic Types of Graft Autograft: Tissue is transplanted back on to the original donor. Isograft: Graft between two individuals with same genetic make-up, i.e. between twins. Allograft: Graft between allogeneic individual i.e. members of same species but of different genetic constitution, e.g. man to man and one mouse strain to another. Xenograft: Graft between two different species, e.g. horse to man. Types of Graft Rejection Hyperacute Rejection It occurs within minutes of transplantation and occurs in individuals with pre-existing humoural antibody. Acute Early Rejection This takes place within 10 days of transplantation and is characterised by dense cellular infiltration. It appears to be a cell mediated hypersensitivity reaction involving T cells. Insidious and Late Rejection This is seen in rejection of kidney allografts when subendothelial deposits of Ig and C3 take place on glomerular basement membrane. Graft Versus Host (GVH) Rejection This reaction may develop when immuno-competent tissues are transferred to an immunologically handicapped host. This type of adoptive immunization results in a host-directed rejection process. GVH may occur under natural circumstances when maternal lymphoid tissues are transferred to the foetus during pregnancy. These can also be induced artificially when adult tissues are injected into unborn or newborn animals or when lymphoid tissue is transferred to adults who have been irradiated or heavily immuno-suppressed with chemical agents. The situation in newborn or foetal animal results into failure of the animal to grow, splenomegaly, diarrhoea and anaemia. This is called as “runt disease” and is often fatal. Mechanism of Graft Rejection There is considerable complexity of action and interaction of cellular and humoural factors in graft rejection. Lymphoid cells play primary role in first set rejection. This is consistent with the histology of the early reaction. Prevention of Graft Rejection

Matching tissue types: The rejection can be minimized by matching graft and recipient in terms of MHC antigen in much the same way the individuals are cross-matched for blood transfusion. Of the different loci, matching of DR locus is more important than any other locus. This matching is also known as histocompatibility testing which can be performed by: • Microcytotoxicity test • Mixed lymphocyte culture. Use of immunosuppressants: Graft rejection can be delayed or avoided by the use of agents which interfere with the induction or expression of immune response. Antigen specific depression of allograft reactivity: To avoid generalised immunsuppression and its resultant complications, efforts are being made to develop approaches by which only specific immune response against graft is reduced significantly leaving rest of the immunological apparatus intact. Immunological Enhancement This mechanism operates in the survival of kidney grafts. It is based upon the observation that deliberates immunisation of animals with irradiated tumour cells produces enhancing antibodies which prolong the life of the tumour. Comparable manipulations can also enhance the survival of kidney graft through this anti-idiotype enhancing antibodies. Clinical Experience in Grafting Privileged sites: Corneal grafts survive without the need for immuno-suppression; as they are avascular they do not sensitize the recipient although they become cloudy if the individual had been pre-sensitised. Grafts of cartilages are successful in the same way. Kidney grafts: Kidney transplantation has now become a common practice. If HLA-D loci of donor and recipients match, a graft survival of 5 years or more has been observed. It is believed that if HLA-B and HLA-A loci also get matched; the survival rate can be prolonged. Administration of multiple blood transfusions prior to grafting has been shown to have a significant beneficial effect on survival. Heart transplant: More than 80% of heart transplants now survive for more than one year. A good HLA-D matching (with not more than single DR mismatch) can give survival of 3 years or more. Liver transplant: With the combined use of cyclosporin and steroid therapy, success rate of liver transplants is now as good as that of heart transplants. Bone marrow grafting: Successful results with bone marrow transfers have been obtained in certain immunodeficiency disorders and aplastic anaemia. An extremely high compatibility between donor and recipient is a must otherwise a fatal graft versus host reaction may take place. Siblings offer the best chance of finding a matched donor.

TUMOUR IMMUNOLOGY For the host, there should not be any difference between a graft and a tumour because both present with a set of antigens which is different than that of the host. In transplantation the whole immune system comes into action to reject the graft. Paradoxically, in malignancy, the host's immune response is either not fully activated and fails to reject the tumour tissue or develops in such a way that growth of the tumour is not only permitted it is even encouraged. Tumour Antigens Followings are considered the immunological expression of tumours: • Antigen induced by chemicals • Antigen induced by virus • Carcinofoetal antigens • Carcinofoetal enzymes Antigens Induced by Chemicals

With chemically induced turnours different antigens appear. These new antigens are different for each tumour. Even two anatomically distinct tumours induced on a single mouse by the same chemical carcinogen will be antigenically distinct Antigens Induced by Viruses Viral induced tumours express unique antigens which unlike those induced by chemicals, are antigenically constant from specimen to specimen. This constant expression of identifiable antigens is a useful diagnostic aid. The DNA viruses which can code for new antigens in hosts are herpes viruses, adenoviruses and the papova viruses. The RNA viruses include Rous Sarcoma virus and mouse mammary turnour virus. Three types of antigens associated with viral transformed cells are: • Those which are associated with infective virion • The tumour (T) or nuclear antigen • The tumour specific transplantation antigen (TSTA) or cytoplasmic membrane antigens. The T antigens are located in the nucleus and are specific for inducing virus and not the malignant cell. The TSTA are important as these come in contact with immune system. Antibodies to these antigens are found in circulation in tumour bearing animals. However, the titre of these antibodies does not correlate well with resistance to tumour or regression of tumour. Carcinofoetal Antigens The antigens are synthesised by the body when there is a cancerous growth to express a metabolic shift from an adult to an immature pathway of protein synthesis. They are as follows: • Carcinoembryonic antigen • Alpha fetoprotein • Alpha 2 hepatic protein Carcinoembryonic antigen: This antigen has been detected by radioimmunoassay (RIA) in tumours of colon, small intestine, liver, stomach, etc. but not in normal tissues surrounding these growths. This antigen was also found in human embryonic gut and gut associated organs during the first two trimesters, after which the antigen becomes more difficult to detect. Because of these facts, it was named as carcinoembryonic antigen (CEA). The normal adult blood level of CEA is about 2.5 mg / L. Levels significantly higher than these are a good index of cancer. CEA gets elevated almost three months prior to the development of clinical features of cancer. Continuous high levels, even after therapy, denotes a poor prognosis. Presence of CEA is not diagnostic of tumour and this is because of two reasons: (a) its presence in many nonmalignant conditions, e.g. cirrhosis liver, cigarette smoking and chronic lung disease and (b) its absence in a large number of cases with confirmed carcinomas of the digestive tract. Alpha fetoprotein (AFP): This is present in foetal serum in very high concentration of 3000 mg/ml. In pregnant woman the level may be upto 500 mg/ml whereas in normal adult it is 5-10 mg/ml. The detection of AFP, like that of CEA is of potential diagnostic and prognostic significance in human oncology. Another successful use of AFP is in the monitoring of neural tube malformations (spina bifida) in fetuses by measuring the AFP level in amniotic fluid which is normally 1.5 to 26 mg / ml at the fifteenth week of gestation. Excesses of this concentration correlate well with serious defects including anencephaly. Alpha 2 hepatic protein (AHP). This is a globulin with high iron content and was earlier found to be associated with hepatoma. Subsequently it could be extracted from the liver of patients who had malignancies at anatomical sites other than liver. Although 50% of patients with malignancies have detectable AHP in their serum, 20% of patients with non-malignant diseases are also positive. Carcinofetal Enzymes Several enzymes described as carcinoplacental or carcinoembryonic enzymes and originating from trophoblastic tissues have been associated with a broad range of cancers. Regan isozyme of alkaline phosphatase is the best known of these which is present in sera of individuals with various forms of cancers and is not restricted to those with placental or trophoblastic tissue tumours. Other isozymes associated with cancerous states include aldolase, glycogen phosphorylase, glucosamine 6phosphate synthetase and amino acid transaminase

Clinical evidence of immune response in malignancy • Higher incidence of malignancies in immunodeficient individuals. • Spontaneous regression of established tumours such as neuroblastoma or malignant melanoma. • Histological evidence of immune response is provided by the presence of lymphocytes, plasma cells and macrophages in the infiltrating tumours. • Dramatic cures following chemotherapy shows the contributory role of immune response. Immunological Surveillance Immunological surveillance means that cell mediated immunity should "seek and destroy" malignant cells that arise by somatic mutation. Hence immune system is expected to maintain a constant 'vigil'. The development of tumours appears to be a lapse in immune surveillance. The possible explanations of this immunological lapse could be: • Due to faster rate of tumour growth some cells might sneak through the immune surveillance mechanism. • Once the tumour reaches a particular size, it may be beyond the capacity of immune surveillance. • The tumour antigens may be covered by antigenically neutral substance and may not be detected by immune system. • Circulating tumour antigens may coat the lymphoid cell and prevent their action. • Some tumours may be of low immunogenicity • Some tumours may form cytokines which suppress cell-mediated immunity. Immunotherapy of Cancers Approaches: • Passive immunotherapy: Using antisera prepared by immunising animals with tumour biopsy proved unsuccessful. Monoclonal antibodies to tumour may play a role as carriers in transporting cytotoxic or radioactive drugs specifically to the tumour cells. • Specific active immunotherapy: By the injection of tumour cell vaccines was tried early in the last century but without success. • Nonspecific active immunotherapy: Employing BCG vaccine and non-living Corynebacterium parvum have proven useful. Intralesinal BCG in malignant melanoma has been reported to induce complete remission. • Specific adoptive immunotherapy: Has been tried with transfer factor, lymphocytes and immune RNA. The donors have been the persons who have been cured of these neoplasms. Immunotherapy is not very effective in the presence of large tumour cells. It is best used along with surgery, radiotherapy and chemotherapy.