The Relative Contribution of Intrathyrmic Inoculation of Donor Leukocyte Subpopulations in the Induction of Specific Tolerance

Abstract

We have recently demonstrated that intrathymic (IT) inoculation of ultraviolet-B irradiation-modified donor spleen cells induces specific tolerance to organ allografts in transiently immunosuppressed adult rats. This study examines the splenic leukocyte component that plays a role in the induction of organ-specific tolerance when injected into the thymus of an adult animal. Our results showed that in the low responder combination of Lewis-to-ACI, IT inoculation of resting Lewis T-cells consistently induced specific unresponsiveness to cardiac allografts in sublethally irradiated (200 rad total body irradiation) ACI recipients while the same was true in the high responder rat combination of WF-to-Lewis, where recipient rats were transiently immunomodulated with antilymphocyte serum. In contrast, IT inoculation of donor B cells, macrophages, or dendritic cells in similarly prepared animals failed to prolong graft survival in both the low responder (Lewis-to ACI) and the high responder (WF-to-Lewis) rat strain combinations. This observation suggests that donor-specific unresponsiveness can be readily achieved by IT inoculation of major histocompatability (MHC) class I expressing donor-type resting T-cells rather than by any donor-type antigen presenting cells that express MHC class I and II molecules. Extrathymic inoculation of T-cells in transiently immunosuppressed recipients failed to prevent graft rejection, thus demonstrating the privileged position of the thymus in the induction of tolerance. The unresponsive recipients of cardiac allografts specifically and permanently accepted donor-type second-set islet allografts, thus confirming antigen-specific tolerance in this model. These results suggest that manipulation of the immune system through thymic reeducation of the developing T-cells by the deliberate introduction of foreign MHC class I cellular alloantigens has therapeutic potential in the induction of transplantation tolerance in adult animals.