FK 506: a novel immunosuppressant for treatment of autoimmune disease: Rationale and preliminary clinical experience at the University of Pittsburgh

FK 506 (Prograf) is a novel macrolide antibiotic isolated from the soil fungus Streptomyces tsukubaensis [24]. Although it is totally distinct in molecular structure from cyclosporin (CsA) (Sandimmune), a cyclic endecapeptide extracted from the fungus Tolypocladium inflatum (Fig. 1), the two drugs share a remarkably similar, selective inhibitory action on the activation and proliferation of CD4+ T helper (TH) lymphocytes [25, 41, 50, 51, 56]. These cells play an essential, central role both in antigen recognition and as the sources of soluble, hormone-like mediators (cytokines) of the cascade of events leading to the expression of immune reactivity. By inhibiting the activation of CD4+ TH cells, FK 506, like CsA, exerts a wide-range of immunosuppressive activities. It is recognized that both drugs prolong solid-organ allograft survival in experimental animals and in man. FK 506, however, is considerably more powerful as an antilymphocytic agent than CsA, as evidenced by the superior potency of the former drug in inhibiting antigen-driven T cell activation, cytokine production and lymphocyte proliferation in vitro [50]. Moreover, the systemic levels of FK 506 required to induce and maintain immune suppression are approximately 100-fold lower than are the blood levels of CsA to achieve the same effect. The immunosuppressive efficacy of CsA in man (in renal transplant recipients and patients receiving bone marrow transplants) was first reported in 1978; in 1989, the first account of the ability of FK 506 to prevent or reverse organ allograft rejection was published [44]. Data obtained over the last 3 years provide good clinical evidence that FK 506 exhibits a narrower range of side effects than does CsA and that, as compared with CsA, FK 506 has greater steroid-sparing activity [45, 46]. Whilst the potential benefits of FK 506 for the prophylaxis and reversal of organ allograft rejection (in particular liver transplant rejection) are becoming recognized, the value of the drug in the treatment of autoimmune disorders is now also beginning to be assessed. In this article (1) a rationale for the use of FK 506 in autoimmune disease, (2) a description of its molecular action and immunosuppressive activities, (3) a consideration of the biological and pharmacological properties of FK 506, (4) a review of its capacity to inhibit a wide variety of experimental autoimmune disorders, and (5) a report on the early clinical experience with FK 506 in the clinical management of a panoply of autoimmune disease seen at the University of Pittsburgh Medical Center (UPMC) will be presented. Moreover, a brief outline of laboratory investigations utilized to monitor the status of T lymphocytes in these patients and a discussion of the side effects of FK 506 will be presented. Throughout, we shall draw upon comparisons between FK 506 and CsA which have been documented in the literature. Fig. 1 The molecular structure of the immunosuppressive macrolide FK 506 (mol. wt. 822 daltons) and of the less powerful, but similarly acting cyclic endecapeptide cyclosporin A (mol. wt. 1203 daltons) Rationale for the use of FK 506 in autoimmune diseases The role of T cells in autoimmunity The therapeutic use of FK 506 in the treatment of autoimmune disease is based on the premise that all of these disorders are T cell driven [39]. It is, therefore, important to examine the evidence that activated CD4+ TH cells and their cytokine products are important both in the induction and maintenance of various diseases such as psoriasis, uveitis, insulin-dependent type-1 diabetes, chronic active hepatitis-autoimmune (CAH-A), rheumatoid arthritis and multiple sclerosis – diseases that are currently being treated with FK 506. In uveitis [11], type-1 diabetes [6], multiple sclerosis [16] and psoriasis [3] for example, T cells are believed to play an important pathogenic role. Much of the evidence to support this view comes from studies in experimental animal models and from in vitro investigations of the adverse or destructive interactions between T cells, antigen-stimulated cytokines and the target tissue affected by the disease process. In the autoimmune liver diseases [26], CAH-A and primary biliary cirrhosis (PBC), and in rheumatoid arthritis [9], there is abundant evidence for the involvement of T cells in the pathogenesis of each disease and, therefore, a rationale for the use of FK 506 in each exists. In recent years the therapeutic efficacy of CsA in uveitis, psoriasis, PBC, CAH-A, and rheumatoid arthritis has been demonstrated [52]. Moreover, CsA has been shown to alter the natural history of type-1 diabetes [4]. The drug has not, however, made a significant impact upon the clinical management of patients with most of these diseases. In autoimmune diseases such as systemic lupus erythematosus (SLE) or the nephrotic syndrome, the rationale for the use of CsA or FK 506 is less clear. Thus, in SLE, humoral immunity appears to be more important than cellular immunity in the pathogenesis of the disease, and in idiopathic nephrotic syndrome the pathogenic mechanisms responsible for the disease process are far from clear. Nevertheless, in nephrotic syndrome, T cell dysfunction, recruitment of B cells, immunoglobulin deposition within the kidney and a central role for lymphokines have been implicated by various authors [7, 8, 18, 54]. Moreover, CsA has been shown to be very effective in the steroid-sensitive nephrotic syndrome, although less so in steroid-resistant patients [52]. A spectrum of autoimmune disorders is shown in Table 1. The predicted efficacy of FK 506 in their treatment is based on the assumption that the role of T cells in these various disease processes is central, and also on experience in animal models of these diseases with either CsA or FK 506. Account is also taken of clinical experience with CsA in these autoimmune disorders. Table 1 Possible mechanisms of autoimmune diseases and predicted responses to FK 506a Evidence that autoimmune diseases are T cell driven There is a large body of additional experimental data which provides supportive evidence to the thesis that autoimmune diseases are driven by T cells and their cytokine products. In addition to the proven efficacy of CsA or FK 506 in many experimental autoimmune diseases, antibodies directed against CD4+ T cells or against the interleukin 2 receptor (IL-2R; expressed on activated T cells) have been shown to be effective therapeutic agents in these animal models. When stimulated with appropriate antigen or monoclonal antibody, T cell clones derived from lesional tissue or peripheral blood secrete cytokines which effect the pathological changes observed in target tissue (e.g., fibroblasts in scleroderma, keratinocytes in psoriasis or islet cells in type-1 diabetes) that are relevant to the disease process observed in vivo. Such antigen-stimulated T cell clones can induce disease when transferred to healthy recipients (e.g., induction of type-1 diabetes, experimental arthritis or allergic encephalomyelitis). Furthermore, in many experimental models of autoimmunity, it can be shown that neonatal thymectomy has a pronounced beneficial effect in preventing development of the disease. For references and discussion see [40].