FK 506 and autoimmune disease: perspective and prospects.

Abstract

Four classes of drugs have been used as immunosuppressive agents in human autoimmune diseases—corticosteroids, alkylating agents (cyclophosphamide and chlorambucil), antimetabolites (azathioprine and methotrexate) and more recently, cyclosporin A (CsA). Before the introduction of CsA within the last decade, the successful use of immunosuppressive drugs in autoimmune disease was restricted to systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis and nephrotic syndrome. CsA, which acts selectively to inhibit T cell activation and cytokine production has changed the situation. Now, using CsA, significant improvement in a higher proportion of patients than previously observed can be achieved in autoimmune diseases with a presumed T cell pathogenesis. These include psoriasis, uveitis, insulin-dependent (type 1) diabetes mellitus, primary biliary cirrhosis, aplastic anaemia, lichen planus and severe allergic asthma. Autoimmune disorders mediated by autoantibodies however, such as the autoimmune cytopenias, myasthenia gravis, SLE, Graves’ disease and glomerulonephritides are relatively resistant to CsA. In addition to the improved rate of response seen with CsA, opportunistic infections are very rare in CsA-treated autoimmune disease patients. Despite the successes achieved with CsA, however, several problems continue to exist. These are (1) an insufficient response rate, (2) disease recurrence following drug withdrawal and (3) the associated risks of drug toxicity or excessive immunosuppression. The most common side effects are infections, lymphoproliferative disease, nephrotoxicity including arterial hypertension, cosmetic deformity with hirsutism and coarsening of the facies, hypercholesterolemia and an increased disposition to diabetes mellitus. These difficulties have driven the search for new agents that act with precision on those components of the immune system involved in disease pathogenesis but not on therapeutically irrelevant cells. Amongst the most promising new candidate drugs is FK 506. Already the advent of FK 506 and its use as an investigational tool has had a major impact on our understanding of molecular mechanisms underlying T cell activation and at a clinical level, on the practice of organ transplantation. Its efficacy in the prevention of allograft rejection is well documented; more germane to the auto-immune field is its ability to reverse established rejection which is thought to follow the same mechanisms as many autoimmune diseases. In this context, the rejecting organ graft (or bone marrow) may be thought of as a direct analogue of many autoimmune disorders.