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inhibition of Immune Responses

Both the prevention of transplant rejection and the treatment of autoimmune disorders call for a suppression of immune responses. However, immune suppression also entails weakened defenses against infectious pathogens and a long-term increase in the risk of neoplasms.

A specific immune response begins with the binding of antigen by lymphocytes carrying specific receptors with the appropriate antigen-binding site. B-lymphocytes "recognize" antigen surface structures by means of membrane receptors that resemble the antibodies formed subsequently. T-lympho-cytes (and naive B-cells) require the antigen to be presented on the surface of macrophages or other cells in conjunction with the major histocompatibility complex (MHC); the latter permits recognition of antigenic structures by means of the T-cell receptor. T-help-er cells carry adjacent CD-3 and CD-4 complexes, cytotoxic T-cells a CD-8 complex. The CD proteins assist in docking to the MHC. In addition to recognition of antigen, activation of lymphocytes requires stimulation by cytokines. Interleukin-1 is formed by macrophages, and various interleukins (IL), including IL-2, are made by T-helper cells. As antigen-specific lymphocytes proliferate, immune defenses are set into motion.

I. Interference with antigen recognition. Muromonab CD3 is a monoclonal antibody directed against mouse CD-3 that blocks antigen recognition by T-lymphocytes (use in graft rejection).

II. Inhibition of cytokine production or action. Glucocorticoids modulate the expression of numerous genes; thus, the production of IL-1 and IL-2 is inhibited, which explains the suppression of T-cell-dependent immune responses. Glucocorticoids are used in organ transplantations, autoimmune diseases, and allergic disorders. Systemic use carries the risk of iatrogenic Cushing's syndrome (p. 248).

Cyclosporin A is an antibiotic polypeptide from fungi and consists of 11, in part atypical, amino acids. Given orally, it is absorbed, albeit incompletely. In lymphocytes, it is bound by cyclophilin, a cytosolic receptor that inhibits the phosphatase calcineurin. The latter plays a key role in T-cell signal trans-duction. It contributes to the induction of cytokine production, including that of IL-2. The breakthroughs of modern transplantation medicine are largely attributable to the introduction of cyclo-sporin A. Prominent among its adverse effects are renal damage, hypertension, and hyperkalemia.

Tacrolimus, a macrolide, derives from a streptomyces species; pharmacologically it resembles cyclosporin A, but is more potent and efficacious.

The monoclonal antibodies daclizu-mab and basiliximab bind to the a-chain of the II-2 receptor of T-lympho-cytes and thus prevent their activation, e.g., during transplant rejection.

III. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclo-phosphamide (p. 298). The antipro-liferative effect is not specific for lymphocytes and involves both T- and B-cells.

Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate dehydrogenase, which catalyzes purine synthesis in lymphocytes. It is used in acute tissue rejection responses.

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