TOLERANCE INDUCTION TO RAT ISLET ALLOGRAFTS BY INTRATHYMIC INOCULATION OF DONOR SPLEEN-CELLS

Intrathymic (i.t.) injection of UVB donor spleen cells induces donor-specific unresponsiveness to cardiac and islet allografts in sublethally irradiated recipients in the low-responder Lewis-to-ACI rat combination. This study examined whether unresponsiveness to islet allografts could be achieved following i.t. inoculation of untreated or UVB-irradiated donor SC under the cover of peritransplant immunosuppression with sublethal TBI or ALS in the high-responder combination of WF-to-lewis rats. The results of this study show that i.t. injection of untreated SC combined with sublethal TBI or ALS led to permanent islet allograft survival in 50% of recipients, while i.t. injection of UVB donor SC combined with sublethal TBI or ALS resulted in indefinite graft survival in 80-100% of recipients. Third-party (BN) islets were rejected normally in this model, confirming donor-specificity of unresponsiveness. Extrathymic inoculation of UVB-treated donor SC by the subcutaneous, intratesticular, or intravenous routes in similarly immunosuppressed animals did not result in any prolongation of islet allograft survival, thus confirming the importance of the thymus in induction of tolerance in this model. The unresponsive recipients that were challenged with 2nd-set allografts 100 days after islet transplantation, permanently accepted donor-type but not third-party (ACI) cardiac allografts, thus proving that recipients are indeed tolerant to donor alloantigens and that such tolerance is donor- and not organ-specific. This study proposes a novel strategy of immunomodulation that may be useful in induction of specific unresponsiveness to organ allografts.