Recently, we showed that intrathymic (i.t.) injection of UVB-irradiated (600 J/m2) spleen cells induces donor-specific unresponsiveness to cardiac allografts in the sublethally irradiated (200 rads, TBI) recipients in the Lewis-to-ACI rat combination. This study examined if i.t. injection of UVB donor SC could induce specific unresponsiveness to neovascularized (islet) allografts in the same rat combination of Lewis-to-ACI. Streptozotocin-induced diabetic ACI rats pretreated with sublethal TBI (200 rads) 7 days prior to intraportal transplantation of freshly isolated Lewis islets reject their grafts in 10.2 +/- 2.9 days compared with rejection of islets in 8.5 +/- 2.6 days in unmodified controls. Recipient pretreatment with i.t. injection of UVB donor SC combined with sublethal TBI (200 rads) 7 days prior to islet transplantation induced indefinite graft survival (> 200 days) in 3 of 7 animals. Similar treatment failed to prevent acute rejection of third-party (WF) islets, thus demonstrating donor-specificity. Treatment with sublethal TBI (200 rads) on the day of islet transplantation led to permanent graft survival in 2 of 5 animals that received i.t. inoculation of UVB donor SC 7 days prior to islet transplantation. Conditioning of the recipients with a sublethal TBI dose of 300 rads on the day of islet transplantation, which alone delayed graft rejection for only 19 days, led to indefinite graft survival (> 150 days) in all animals pretreated with i.t. injection of UVB donor SC. Extrathymic inoculation of donor UVB SC via subcutaneous, intraperitoneal, intratesticular, and intravenous routes, respectively in similarly prepared animals failed to prolong islet survival, thus confirming the privileged position of the thymus in the induction of tolerance. Our findings suggest that this new strategy of immunomodulation with donor UVB SC is potentially useful for induction of donor-specific unresponsiveness.