Prolonged survival of human islet xenografts under the kidney capsule of diabetic rats was achieved. Human islet xenograft survival time for the nonimmunosuppressed and single-dose antithymocyte serum-treated rats were 3.7 +/- 0.33 days (mean +/- SE, n = 6) and 4.2 +/- 0.63 (n = 4), respectively. In the recipients given 5 doses of ATS after islet transplantation, the graft survival time was significantly prolonged to 18.2 +/- 1.9 days (n = 6). An intravenous glucose tolerance test was performed on 3 recipients with a functional graft 12 days after xenotransplantation. The mean K rate was 1.44 +/- 0.43 (n = 3) compared with that of 2.1 +/- 0.14 (n = 5) found in normal control rats. Human C-peptide was present in the rat recipients following islet transplantation. In addition all 3 recipients showed significant basal human C-peptide values posttransplant and achieved levels of above 2.4 ng/ml during IVGTT. Morphologic and immunohistochemical examination of the islet grafts show that in recipients without immunosuppression or with a single dose of ATS, there was marked degree of fibrosis with little endocrine tissue left in the graft area by day 5. In contrast, the xenograft from recipients treated with 5 doses of ATS still contained well-preserved islet tissue with many insulin and glucagon containing cells on the day of graft removal when blood glucose had returned to the hyperglycemic level. Infiltration of the graft area with lymphoid cells (OX1+, OX8+, and W3/25+) was prominent, but they were not detected within the islets. Staining with monoclonal antibody clone L243 did not detect any expression of human class II antigen on the human pancreatic endocrine cells undergoing rejection by the host. This study has shown that with adequate immunosuppression human islet xenograft can normalize the blood glucose with prolonged survival time in diabetic rat recipients. The discordant xenotransplantation model used in this study would be useful for future xenotransplantation studies.