FK506 in experimental renal allografts in dogs and primates

The immunosuppressive potency in renal allografts and the toxicity of FK506 (FK) in two large animal models, the dog and baboon, are reported. FK is a fermentation product isolated from Streptomyces tsukubaensis that has been shown to be immunosuppressive both in vitro and in rats where it has prolonged skin, heart, and kidney allografts. In dogs FK has serious side effects due to a widespread vasculitis at a dose that was only minimally immunosuppressive. When FK was given to renal allograft recipient dogs at the minimally immunosuppressive dose of 0.5 mg/kg orally daily together with cyclosporine A, 10 mg/kg orally daily, the severe vasculitic lesions were still seen in three of four animals at days 5, 9, and 22. In baboons FK proved to be a powerful immunosuppressive agent but with a serious side effect that required dose reduction to a nonimmunosuppressive level to prevent a diabetogenic effect. The presence of insulin granules within the islets and raised levels of circulating insulin suggests a possible peripheral insulin resistance induced by FK that is reversible by dose reduction. Although FK is immunosuppressive, it appears to induce various significant side effects in the different species we have studied. A reliable assay of blood drug levels may have been beneficial in allowing adjustment of the dose. This should be made available during any future studies.