Biology of Disease

it is probable that the recipient already has antibodies against graft antigens

and the donor is unlikely to be a suitable match.

Matching donor and recipient

Individuals inherit a set of HLA genes from each parent. Thus, siblings are

more likely to have a closer match than unrelated donors and, occasionally,

people have donated a healthy kidney to a sibling with renal failure. Other

sources of kidneys for transplantation include cadavers, often people who

have been killed in accidents. The HLA types of potential recipients are stored

in computer databases so that when a kidney donor becomes available, they

can be HLA typed and the kidneys given to those recipients whose HLA anti-

gens match as closely as possible.

Retrospective studies on the outcome of kidney transplantation have shown

that matching the donor to the recipient improves graft survival. Thus, in

the most favorable match, that is no mismatches of the HLA-DR, HLA-A and

HLA-B alleles graft survival is superior to those with no mismatch of HLA-

DR and only one mismatch of HLA-A and/or HLA-B alleles. These also gave

significantly better graft survival than any other mismatched graft.

6.13 Immunosuppression

All patients who receive an allograft are liable to reject the transplant, even

if the recipient and host are closely matched for histocompatibility antigens.

This is because relatively few of the HLA antigens are tested for, and complete

matches are rare. Thus, all patients who receive an allograft have to take immu-

nosuppressive drugs to prevent rejection resulting from an immune response.

Immunosuppressive treatments fall into a number of categories. The first gen-

eration of immunosuppressive drugs were used to prevent lymphocytes from

proliferating (Table 6.15). As these drugs act by inhibiting cell division, they

are also used in the treatment of cancer. Their actions are described in more

detail in Chapter 17. Corticosteroids, such as cortisol, are also immunosup-

pressive agents but act principally by suppressing inflammation. They are still

used, often in combination with other drugs such as methotrexate. All the first

generation drugs produce a ‘blanket’ immunosuppression and prevent all

immune responses. This makes the patient more susceptible to infections of

all kinds, but especially to opportunistic infections caused by such organisms

as Candida albicans. Immunosuppressed patients are also more susceptible

to the types of cancers associated with viruses, including lymphoma, associ-

ated with the Epstein-Barr virus (EBV ) and Kaposi’s sarcoma, associated with

the Kaposi’s sarcoma associated herpes virus (KSV ). First generation immu-

nosuppressive treatments also have significant toxicity, because they affect all

dividing cells, including those of the bone marrow and of the GIT. Some, such

as methotrexate, also show liver toxicity.

Type of treatment Mechanisms of action Examples

Purine analogs incorporated into DNA during the process of DNA

synthesis; prevent further DNA elongation

azathioprine;

mercaptopurine

Folic acid antagonists prevent the action of dehydrofolate reductase, an

enzyme required for the synthesis of purines and

pyrimidines

methotrexate;

aminopterin

Alkylating agents become incorporated into developing DNA and cross-

links DNA strands, preventing further replication

cyclophosphamide

Table 6.15First generation immunosuppressive drugs

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