THROMBOXANE A(2) RECEPTOR BLOCKING ABROGATES DONOR-SPECIFIC UNRESPONSIVENESS TO RENAL-ALLOGRAFTS INDUCED BY THYMIC RECOGNITION OF MAJOR HISTOCOMPATIBILITY ALLOPEPTIDES

Recent in vitro studies have documented that thromboxane (Tx)A(2) indu ces thymocyte apoptosis by acting on specific receptors abundantly exp ressed on the surface of immature T lymphocytes. No information is ava ilable on the in vivo relevance of this observation in development of self- or acquired tolerance. We and others have previously documented that injection of donor cells into adult thymus of experimental animal s induced specific systemic unresponsiveness to allografts in the rat and mouse models. More recently, we have shown that intrathymic inject ion of synthetic class II major histocompatibility complex (MHC) allop eptides resulted in donor-specific unresponsiveness to renal allograft s. The induction of unresponsiveness was abrogated by recipient thymec tomy within the first week. We now report the effect of TxA(2) blockad e on acquired thymic tolerance to renal allografts induced by intrathy mic injection of synthetic class II MHC allopeptides in the Wistar-Fur th (WF) to Lewis rat strain combination. Administration of the TxA(2) receptor blocker prior to transplantation or 2 wk postengraftment comp letely abrogated the unresponsive state. In addition, inhibiting the T xA(2)-forming enzyme by aspirin or dexamethasone also abolished the in duction of acquired thymic tolerance. Evidence is also provided for a critical ''dose'' of peptides to be injected into the thymus to induce systemic unresponsiveness to renal allografts. These data, coupled wi th observations that activated peripheral T cells can circulate throug h the thymus, provide evidence that TxA(2)/TxA(2) receptor interaction in the thymic microenvironment, leading to anergy/programmed cell dea th of activated T cells, may play an important role in the development of acquired unresponsiveness in vivo.