Thymus: a direct target tissue in graft-versus-host reaction after allogeneic bone marrow transplantation that results in abrogation of induction of self-tolerance.

Abstract

Graft-versus-host reaction (GVHR) following allogeneic bone marrow (BM) transplantation was investigated by analyzing expression of antigen receptors on T cells specific for recipient antigens. GVHR chimeras were prepared by transplanting mixtures of splenic T cells and T-cell-depleted BM cells from B10 (I-E-, Mls-1b) or B10.AQR (I-E+, Mls-1b) mice into lethally irradiated AKR/J (I-E+, Mls-1a) recipients. Increased proportions of V beta 6+ T cells reactive to recipient antigens (I-E and Mls-1a) were observed in thymuses from such chimeras 1 or 5 wk after BM transplantation. V beta 6+ T cells observed 1 wk after BM transplantation were derived from mature T cells that had been inoculated into recipients. These cells responded to recipient antigens expressed in the thymus. After 5 wk, thymocytes brightly positive for V beta 6+ were shown not to descend from mature T cells but to differentiate from precursor cells present in the BM inocula. Since V beta 6+ T cells were eliminated in thymuses from non-GVHR chimeras 5 wk after BM transplantation using T-cell-depleted BM cells alone, it appears that GVHR occurring in the thymus at an early stage abrogates thymic stromal functions essential to induction of self-tolerance in the T-cell repertoire. These findings propose a mechanism (autoimmunity) to explain in part the pathogenesis of chronic GVHR.