Tacrolimus and Therapy of Human Autoimmune Disorders

Tacrolimus (formerly known as FK506) is a macrolide antibiotic isolated from the soil fungus Strtptomyus tsukubamsis. 1 Although it is totally distinct in molecular structure from cyclosporine A (CsA), a cyclic endecapeptide extracted from the fungus Tolypociadium inflatum, the two immunosuppressants share a remarkably similar, selective inhibitory action on the activation and proliferation of CD4> T helper (TH) lymphocytesz.6 (see also chapter 10.3). In 1989, the first account of the ability of tacrolimus to prevent or reverse human organ allograft rejection was publishedJ Data obtained over the ensuing 5 years have provided good evidence that tacrolimus is at least as valuable an investigational tool and clinical immunosuppressive agent as CsA. 8.9 Multicenter, prospective. randomized controlled trials of tacrolimus versus CsA in primary liver transplantation have shown significantly reduced rates of acute rejection and reduced steroid requirements in the tacrolimus arm of the trials. In April 1994, tacrolimus was approved by the US Food and Drug Administration for the therapy of liver allograft rejection. Whilst the potential benefits of tacrolimus in organ transplantation are now widely recognized. the prospective value of the drug in the treatment of autoimmune disorders is now also being assessed. In this chapter. we discuss the rationale for the use of tacrolimus in autoimmune disease. and report on the early clinical experience with the drug in the management of a variety of autoimmune diseases conducted principally at the University of Pittsburgh Medical Center (UPMC) (Table 10.8.1).