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Since intrathymic (i.t.) injection of UV-B-irradiated spleen cells (SC) or purified resting allogeneic T cells, but not resting B cells, dendritic cells, or macrophages induces specific tolerance in transiently immunosup-pressed recipients, we hypothesized that presentation of donor MHC peptide Ag by the host thymic APCs may convey a tolerogenic signal to the recipient. This study examined if i.t. inoculation of allogeneic soluble Ag obtained from 3 M KC1 extracts of purified resting T cells can induce specific tolerance to cardiac allografts in transiently 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 Lewis recipients. This finding was reproducible in sub-lethally irradiated (200 rads TBI) ACI recipients of i.t. Lewis soluble Ag. In contrast, ACI cardiac allografts were promptly rejected in ALS-treated Lewis recipients of i.t. WF soluble Ag, confirming the donor specificity of such immunologic manipulation. Extrathymic inoculation of WF soluble Ag via the intravenous route in controls failed to prevent normal graft rejection in ALS-treated recipients. The long-term unresponsive recipients specifically and permanently accepted donor-type, second-set cardiac allografts. The observation that thy-mectomy performed 7 days after i.t. Ag injection led to graft rejection strongly suggests that the early phase of induction of donor-specific tolerance is dependent on the presence of donor alloantigens in the host thymus. This approach may have important clinical therapeutic potential in the induction of transplantation tolerance.