INDUCTION OF DONOR-SPECIFIC UNRESPONSIVENESS TO RAT CARDIAC ALLOGRAFTS BY PRETREATMENT WITH INTRATHYMIC DONOR MHC CLASS-I ANTIGENS

Since intrathymic injection of UV-B-irradiated spleen cells induces do nor-specific unresponsiveness in the sublethally irradiated (200 rads TBI) recipients, while intrathymic injection of naive SC leads to acut e graft rejection, we hypothesized that presentation of MHC class I ra ther than MHC class II antigens to immature T cells in the thymus may convey a tolerogenic signal to the recipient. The present study was de signed to examine if intrathymic injection of naive MHC class I-positi ve resting T lymphocytes can induce antigen-specific unresponsiveness to cardiac allografts in the Lewis-to-ACI rat combination. The results showed that intrathymic injection of resting Lewis T cells consistent ly induced indefinite graft survival (>300 days) in sublethally irradi ated (200 rads TBI) ACI recipients while similar treatment failed to p revent the rejection of third-party (Wister-Furth) cardiac allografts, thus demonstrating the specificity of the immunologic unresponsivenes s to donor alloantigens. Examination of the timing of intrathymic anti gen presentation relative to cardiac transplantation that would achiev e 100% permanent graft survival in the Lewis-to-ACI rat combination sh owed that the optimal time was 7 days before allografting, while perit ransplant and immediate post-transplant intrathymic inoculation of don or T cells was relatively ineffective in the induction of unresponsive ness to donor grafts. We also showed that removal of the antigen-conta ining thymus in the sublethally irradiated recipients with functioning cardiac allografts consistently caused graft rejection if performed e arlier than 21 days after heart transplantation; thymectomy after 21 d ays of organ transplantation did not affect indefinite survival of the grafts. Thus, it appears that the maintenance of peripheral tolerance to the grafts after 21 days of transplantation may be dependent on th e presence of a new clone of antigen-specific tolerant host T cells. T hese results confirm the immunologic privileged position of the thymus in the induction of central and peripheral tolerance, and suggest tha t pretreatment with intrathymic MHC class I alloantigens is potentiall y useful in the induction of unresponsiveness to donor vascularized al lografts in adult animals and in man.