THE INFLUENCE OF TACROLIMUS ON ExPERIMENTAL AUTOIMMUNE DISEASE

Four classes of immunosuppressive drugs have been used to treat human autoimmune diseases: corticosteroids, alkylating agents (cyclophosphamide and chlorambucil), antimetabolites (azathioprine and methotrexate) and more recently, cydosporine A (CsA). Before the advent of CsA, which was approved by the US Food and Drug Administration (FDA) for the therapy of organ allograft rejection in 1983, the successful use of immunosuppressive drugs in autoimmune disease was restricted to a handful of disorders. These included systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis and nephrotic syndrome. The use of CsA, which selectively inhibits T -lymphocyte activation and cytokine production has resulted in a higher rate of improvement than previously observed in those autoimmune diseases with a presumed T cell pathogenesis. These diverse disorders include psoriasis, atopic dermatitis, uveitis, insulin-dependent (type I) diabetes mellitus. primary biliary cirrhosis, aplastic anemia and lichen planus. In contrast. autoimmune diseases that are believed to be mediated primarily by autoantibodies. such as the autoimmune cytopenias. myasthenia gravis. SLE, Graves' disease and the glomerulonephritides are relatively resistant to CsA. In addition to the improved rate of response seen with CsA, opportunistic infections (a potentially serious complication of cytotoxic drug administration) are very rare in CsA-treated autoimmune disease patients. Despite the successes achieved with CsA. several important problems still exist with respect to the immunosuppressive therapy of autoimmune diseases. These include: (1) an insufficient response rate; (2) disease recurrence following drug withdrawal (failure to induce tolerance); and (3) the associated risks of drug toxicity or excessive immunosuppression (including infectious complications and malignancy). With respect to CsA. the most common side effects are nephrotoxicity (including arterial hypertension), cosmetic deformity with hirsutism and coarsening of the facies. hypercholesterolemia and an increased disposition to diabetes mellitus. Resolution of these difficulties has become the incentive for discovery of new immunosuppressive agents that act