INDUCTION OF TRANSPLANTATION TOLERANCE TO RAT CARDIAC ALLOGRAFTS BY INTRATHYMIC INOCULATION OF ALLOGENEIC SOLUBLE PEPTIDES

Since intrathymic (i.t.) injection of UV-B-irradiated spleen cells (SC ) or purified resting allogeneic T cells, but not resting B cells, den dritic cells, or macrophages induces specific tolerance in transiently immunosuppressed recipients, we hypothesized that presentation of don or MHC peptide Ag by the host thymic APCs may convey a tolerogenic sig nal to the recipient. This study examined if i.t. inoculation of allog eneic soluble Ag obtained from 3 M KCl extracts of purified resting T cells can induce specific tolerance to cardiac allografts in transient ly immunomodulated recipients. We have now shown that i.t. inoculation of donor soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0 leads to indefinite WF cardiac allograft survival (>200 days) in Lewi s recipients. This finding was reproducible in sublethally irradiated (200 rads TBI) ACI recipients of i.t. Lewis soluble Ag. In contrast, A CI cardiac allografts were promptly rejected in ALS-treated Lewis reci pients of i.t. WF soluble Ag, confirming the donor specificity of such immunologic manipulation. Extrathymic inoculation of WF soluble Ag vi a the intravenous route in controls failed to prevent normal graft rej ection in ALS-treated recipients. The long-term unresponsive recipient s specifically and permanently accepted donor-type, second-set cardiac allografts. The observation that thymectomy performed 7 days after i. t. Ag injection led to graft rejection strongly suggests that the earl y phase of induction of donor-specific tolerance is dependent on the p resence of donor alloantigens in the host thymus. This approach may ha ve important clinical therapeutic potential in the induction of transp lantation tolerance.