TRANSPLANTATION TOLERANCE TO RAT CARDIAC AND ISLET ALLOGRAFTS BY POSTTRANSPLANT INTRATHYMIC INOCULATION OF SOLUBLE ALLOANTIGENS

The search for strategies for induction of specific tolerance in adult animals that will avoid long-term host immunosuppression with its com plications has led to the deliberate introduction of alloantigens (Ag) into the adult thymus, However, pretransplant intrathymic (IT) inocul ation of alloantigens (Ag), which has consistently induced tolerance t o vascularized and neovascularized allografts in adult rodents, has li mited future clinical application, To overcome the practical Limitatio ns of pretreatment, we have examined in the Lewis-to-WF combination th e effect on graft survival of either simultaneous or posttransplant IT inoculation of soluble Ag obtained from 3M KCI extracts of donor T ce lls in transiently rabbit antirat lymphocyte serum (ALS) immunosuppres sed recipients, While IT injection of 2.0 mg soluble Ag alone on day o f cardiac transplantation caused acute graft rejection, IT inoculation of 2.0 mg Ag combined with 1 ml ALS transient immunosuppression of th e recipient on day 0 led to long-term graft survival (>250 days) in 5/ 6 recipients, Similarly, IT injection of soluble Ag on posttransplant day 3 or day 7 combined with 1 ml ALS on day 0 relative to allograftin g resulted in permanent graft survival in all recipients, In contrast, intravenous injection of soluble Ag combined with ALS immunosuppressi on on day 0 led to acute graft rejection that paralleled the rejection seen in ALS treated controls, Third-party Brown Norway (BN) hearts we re acutely rejected in similarly prepared recipients of IT-Ag, thus co nfirming donor specificity. The long-term unresponsive Wistar-Furth (W F) recipients challenged 100 days after cardiac transplantation with a second-set graft specifically and permanently (>100 days) accepted th e second-set donor cardiac allografts, thus demonstrating donor-specif ic tolerance. In similar experiments, IT inoculation of 2 mg soluble A g combined with transient ALS immunosuppression resulted in donor-spec ific unresponsiveness to islets in the same rat combination of Lewis-t o-WTF. Our findings suggest that this new strategy of immunologic mani pulation of the adult thymus offers a safe, effective, and reproducibl e method of inducing tolerance that may have therapeutic application i n cadaveric organ transplantation.