Pathologic observations in human allograft recipients treated with FK 506.

Abstract

FK 506, a powerful new immunosuppressant, has proved to be an effective drug for the prevention and treatment of allograft rejection in animals.1–8 In some respects, it was even shown to be superior to CyA, which revolutionized solid organ transplantation a decade earlier. However, during trials in experimental animals, serious questions were raised regarding its potential toxicity. Wide-spread arterial necrosis, induction of a diabetic state, and renal tubular and liver damage were among the most worrisome harmful effects attributed to this agent.9–12 These reported toxicities varied with the animal species used. Rats could be given relatively large doses with seemingly little consequence,13 while dogs given the same amounts on a per weight basis experienced vomiting and emaciation, and often died.6 Evidence of a peculiar, noninflammatory necrosis of the media and periadventitia of muscular arteries was found at the time of death in the canine subjects.6,8,9–12 Nevertheless, our group6,8 and Ochiai et al14 noted the same lesions in animals who never received the drug, while some of the other reported side effects were not observed at all.6,8,13 These findings eased some, but not all, of the concern surrounding the use of FK 506 in humans. Encouraged by the promise of this agent and the inconclusive nature of the most serious potential side effects, clinical trials were cautiously undertaken in humans who had already received allografts, but whose organs were failing from rejection under conventional therapy, in which CyA was the mainstay immunosuppressant. In fact, many of these first patients had already lost one or more grafts to rejection. The following report is an account of the pathologic findings in the organ allografts and other tissues from the patients who were the first to be given this drug.