Toxicity of FK-506 in Human Fetal Pancreas

Abstract

The toxic effects of FK-506 (FK), a newly discovered immunosuppressive agent isolated from Streptomyces tsukubaensis, were studied in the human fetal pancreas (HFP) system. Human fetal pancreas explants (14-21 wk gestation) were cultured up to 72 h with either 10(-10) to 10(-7) M FK or 10(-8) to 10(-5) M cyclosporin A (CsA), then examined histologically and functionally with a stimulated insulin-release assay. Additionally, FK and CsA were tested for the ability to suppress cell-mediated immunity with a human mixed-lymphocyte reaction (MLR). Previous studies have demonstrated that near-complete immunosuppression is obtained with FK at 10(-8) M and CsA at 10(-6) M. When cultured up to 72 h throughout the concentration range, neither FK nor CsA altered HFP cellular architecture, and indirect immunoperoxidase staining for insulin demonstrated no change in quantity or distribution of insulin-producing beta-cells compared with control tissue. Drug-cultured HFP also retained the ability to release insulin in response to a glucose/theophylline challenge. Finally, 50% inhibition of a human MLR was achieved with FK at 2 x 10(-9) M and CsA at 2 x 10(-7) M, demonstrating the 100-fold greater potency of FK. Our results suggest that further work with FK will show that this immunosuppressive agent can be used with HFP transplantation into diabetic patients without toxicity to HFP.