Induction of Tolerance to Islet Xenografts in a Concordant Rat-to-Mouse Model

Induction of tolerance to concordant rat islet xenografts (150 Wistar-Furth [WF] islets) in streptozocin-induced (STZ) diabetic mice (C57BU/6) was determined at three different sites for islet implantation (thymus, kidney capsule, and liver). Islets transplanted into the thymus or kidney capsule were either fresh or cultured at 24°C for 7 days, and the mice received a single injection of either anti-mouse lymphocyte serum (MALS) alone or anti-rat lymphocyte serum (RALS) and MALS. Islets transplanted into the liver via the portal vein were cultured at 24°C for 7 days, and the mice received a single injection of MALS and RALS. To document the induction of tolerance, recipients with islet xenografts surviving >100 days were made diabetic again by STZ (thymus and liver) or nephrectomy (kidney capsule) and received a second transplant of 150 fresh WF islets in the kidney capsule. Kidney capsule placement of fresh or cultured islets with MALS alone or MALS and RALS did not induce tolerance in a significant number of recipients. The intrathymic transplantation of fresh or cultured islets with MALS alone resulted in prolonged WF islet xenog raft survival (mean survival time of 39.7 ± 7.9 days) but did not result in tolerance, whereas the administration of MALS and RALS with the intrathymic placement of fresh or cultured islets induced tolerance in ∼50% of the mice. Intrahepatic transplantation of cultured islets with MALS and RALS resulted in tolerance to donor islets in 90% of the recipients. Donor specificity was evaluated by a third major histocompatability complex–disparate fresh Lewis islet xenograft. Approximately 50% of these xenografts were not rejected, suggesting that the tolerance may not be haplotype-specific. The mechanisms involved in inducing tolerance to islet xenografts are not clearly established; however, this study clearly demonstrates that tolerance to xenogeneic islets can be achieved by using a brief period of immunosuppression in the intrathymic or intrahepatic transplantation site, with intrahepatic implantation achieving tolerance in a higher percentage of recipients than the intrathymic site.