Immunology

TRANSPLANTATION AND MALIGNANCY

Classification of grafts:
Types of Grafts

Fresh May be Based on Based on Genetic

living or organ: anatomical Classification:
Or dead site:
material Liver Autograft
Cadaveric Kidney Orthotopic Allograft
Heart (at normal Isograft
Skin site) Xenograft
Heterotropic
(not at
normal site)
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 non-
malignant 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 6-
phosphate 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.