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-1") or B1O.AQR (I-E+, Mls-lb) mice into lethally irradiated AKR/J (I-E+, Mls-1a) recipients.Increased proportions of Vp6' T cells reactive to recipient antigens (I-E and Mls-1la) were observed in thymuses from such chimeras 1 or 5 wk after BM transplantation. Vp6' 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 Vp6+ were shown not to descend from mature T cells but to differentiate from precursor cells present in the BM inocula. Since Vp6' 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.Graft-versus-host reaction (GVHR) has assumed importance with the expanding use of allogeneic bone marrow transplantation (ABMT) to treat diseases for which no alternative therapy exists (1-4). GVHR occurs when mature T cells in the bone marrow (BM) graft react immunologically against histocompatibility antigens of recipient type (5-9). GVHR may have diverse features, depending upon the genetics of donor and recipient, cell populations of donor, and recipient antigen systems (10, 11). Donor CD4+ and CD8+ T cells respond vigorously to antigens of recipient (5,6,12), although these two subsets may play different roles in the pathogenesis of GVHR (6, 12, 13) and may also influence each other (12,14). Despite the development of reagents for definition of T-cell subsets, analysis of GVHR in the combined histopathological and cellular-immunological perspective is hampered by difficulty in determining whether proliferating lymphocytes in different lymphoid regions represent immunologic reactions or whether this lymphoid proliferation merely reflects physiological lymphopoiesis in situ. Another difficulty is the complexity of processes that underlie histopathological changes observed in the lymphoid tissues (15, 16). It has been argued, for example, that during GVHR, stress-induced activation of the pituitary-adrenal axis may lead to hypersecretion of corticosteroid hormones and to thymic involution (17). To simplify further study of GVHR, we sought to determine whether thymus is a direct target of GVHR. MATERIALS AND METHODSMice. AKR/J (AKR) (H-2k, Mls-la) were obtained from The Jackson Laboratory; C57BL/10 (B10) (H-2b, Mls-lb) (AQR), and BlO.BR(BR) (H-2k, Mls-lb) mice were purchased from Shizuok...

T cells become tolerant to self antigens during their development in the thymus. Clonal deletion of thymocytes bearing T cell receptor (TcR) which recognize self antigens is a major mechanism for generating tolerance. In the present study we have used allogeneic bone marrow (BM) chimeras, prepared with various combinations of mouse strains and focusing especially on expressions of I-E molecules and Mls-1a antigens on the cell surface, to investigate both immunohistochemically and by flow cytometry the cell components that contribute to the clonal deletion of T cells positive for V beta 6 TcR. The V beta 6 TcR expression is strongly associated with T cell recognition of both I-E and Mls-1a antigens. We found that I-E+ cells derived from donor BM (and thus not of recipient lineage) represented a primary requirement for deletion of Mls-1a-reactive thymocytes which bear V beta 6 TcR. Immunohistochemical analysis revealed that the donor-derived I-E+ cells were distributed mainly to the thymic medulla and that the V beta 6+ cells were eliminated from the thymic medulla between 2 and 3 weeks following BM transplantation. In contrast, Mls-1a+ cells of either donor or recipient origin might be responsible for the deletion, even though cortical epithelial cells appeared not to express Mls-1a antigens.

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Lethally irradiated SJL/J mice were reconstituted with B10 bone marrow cells, and the process of thymic reconstitution by donor derived cells positive for I‐ A or Vβ8 molecules was investigated. The donor‐derived la+ cells appeared in the medulla on day 7 after reconstitution. The la+ cells became confluent up to day 14, and the cellularity in the medulla on day 17 was almost the same as that in the normal thymus. Dull Vβ8+ thymocytes were first recognized in the cortex on day 10 and were identifiable in the medulla by day 14. The Vβ8+ cells seemed to be mainly CD4+8+ double‐positive. Furthermore, most of the Vg8’cells in the medulla of chimeras given cyclosporin A for 3 weeks after reconstitution appeared to be CD4+8+. The present findings demonstrate that CD4 8+ thymocytes which bear a low concentration of TCR exist in the thymic medulla at a relatively early stage when donor‐derived la+ cells have already settled there. The coincidental appearance and coexistence of la+ cells and TCR+ thymocytes in the medulla suggest that these histological characteristics may be related to the selection of thymocytes in this area.