IMMUNOSUPPRESSANT
IMMUNOSUPPRESSANTS are agents that inhibit the body’s reaction to infection or foreign bodies. In this capacity, drugs with this property may be used to prevent tissue rejection following donor grafting or transplant surgery (though there is then the risk of unopposed infection). Also, immunosuppressants are used to treat autoimmune diseases (where the immune system is triggered into acting against systems in the body), including disorders such as rheumatoid arthritis or lupus erythematosus, and also to treat collagen disorders. These agents include cyclosporin, rapamycin and tacrolimus, cytotoxic agents such as azathioprine and cyclophosphamide. and the glucocorticoids. These will be discussed in turn.
Cyclosporin is technically an antibiotic, which was discovered serendipitously during a search for antifungal agents and is unique in having a selective action on lymphocytes. It is a cyclic peptide of 11 residues – some previously unknown. It is particularly important as an immunosuppressant in limiting tissue rejection during and following organ transplant surgery. It can also be used to treat severe active rheumatoid arthritis and some skin conditions, such as severe resistant atopic dermatitis and (under supervision) psoriasis. It has very little effect on the blood-cell producing capacity of the bone marrow, but has liver toxicity. It works through having a relatively selective action on T-lymphocytes, with several actions, one being at the induction stage, stopping proliferation. Its main effect is to inhibit the synthesis of lymphokines, particularly interleukin-2 (IL-2). It may also inhibit expression at IL-2 receptors on T-cells. It prevents release of histamine from mast cells and blocks transcription of genes for IL-3, IL-4 and LT4. At an intracellular level, cyclosporin binds to a cytosolic protein, cylophilin (one of the immunophilins), and this has the reduction of IL-2 as one end-response.
Rapamycin (sirolimus) is also a natural product, from a soil organism, which is unrelated to cyclosporin but has similar actions, though binding to a different immunophilins. Tacrolimus is a recently introduced macrolide antibiotic similar to cyclosporin, but appears to have a higher incidence of neurotoxicity and nephrotoxicity.
Of the cytotoxic agents azathioprine is the main agent used in immunosuppression to control tissue rejection in transplant surgery. It is converted in the body to mercaptopurine, which is a purine analogue that inhibits DNA synthesis. It inhibits clonal proliferation in the induction phase of the immune response, so suppresses both cell-mediated and antibody-mediated immune reactions. In addition to use in transplant surgery, azathioprine may also be used to treat myasthenia gravis, rheumatoid arthritis, ulcerative colitis and other autoimmune diseases (administration is oral or by injection). Cyclophosphamide is a cytotoxic agent with powerful immunosuppressant action which, after conversion by beta-450, forms a nitrogen mustard intermediate that alkylates DNA and other molecules. Chlorambucil is another alkylating agent that works like cyclophosphamide.
The glucocorticoids are immunosuppressants both by virtue of their antiinflammatory properties and their actions against the immune responses. The basis of these is discussed under other headings: see antiinflammatory agents; CORTICOSTEROIDS; GLUCOCORTICOIDS.
A number of other types of drug are under development. These include agents that interfere with leukotriene synthesis (see LIPOXYGENASE INHIBITORS), interleukin-1 antagonists, monoclonal antibodies linked to cytotoxic drugs etc. See also IMMUNOMODULATORS.
