The effect of a novel immunosuppressive agent, FK506, on fresh islet allografts was evaluated in diabetic rats across major histocompatibility complex (MHC) barriers with respect to the transplantation (TR) site, islet source, treatment regimen, and antidonor antibody (Ab) titers of the recipients after TR. The functional periods of Wistar (Wi) islets transplanted under kidney capsule (KC) or intraportally (IPo) and of a mixture of Wi and Lewis (Le) islets under KC or IPo in nonimmunosuppressed ACI rat recipients were 6.9 +/- 0.4 (n = 7), 6.4 +/- 0.5 (n = 7), 5.6 +/- 0.4 (n = 7), and 6.2 +/- 0.4 (n = 5) days, respectively. FK506 treatment at 1 mg/kg/d intramuscularly (IM) for 2 weeks (protocol I) following islet TR under KC and IPo significantly prolonged the allograft function to more than 71.8 +/- 11.3 (n = 10) and 161.7 +/- 18.6 (n = 11) days, respectively. Additional treatment with FK506 at 1 mg/kg/wk (protocol II) further increased the islet survival under KC to more than 212.6 +/- 22.3 (n = 8) days. With this FK506 treatment protocol, the Wi + Le mixed-islet allograft function was extended to more than 106.1 +/- 10.5 (n = 7) and 167.9 +/- 28.6 (n = 7) days under KC and IPo, respectively. Nephrectomy in 8/8 ACI rats with long-term-functioning Wi (n = 6) and Wi + Le (n = 2) islet allografts resulted in their return to hyperglycemia. Immunohistochemical staining showed abundant insulin-positive cells at the graft site, with small numbers of CD4- and CD8-positive cells present in the vicinity of the normal-appearing islets. Macrophages were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)