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

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