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-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...

Effects of non-major histocompatibility antigens on acute graft-versus-host reaction after allogeneic bone marrow transplantation

“…8,9 It seemed that mismatch at the Mls-1 locus However, BMT mice prepared with a combination of both class I and non-MHC Ag mismatches showed signs between donors and recipients resulted in significant modification of acute GVHR. [10][11][12][13][14][15][16] We report different immunoof clinical GVHR and various cytokines were produced by the spleen cells at an early stage (4 days) after BMT.…”

“…[11][12][13] The V␤6 + T cells appeared to continue proliferating (B10.BR → AKR) 4 days after BMT, which paralleled the increase of V␤6 + T cells in the spleen. In spite of the conbetween 4 and 7 days after BMT but no longer produced IL-4 at day 7 (Figure 2).…”

“…Spleen and thymus cells were stained as (Kyowa Hakko Kogyo, Tokyo, Japan) were cocultured on described elsewhere. [10][11][12] Briefly, in the case of V␤6 staina 96-well flat-bottom culture plate (Falcon; Becton Dickining, cells were first reacted with anti-V␤6 moAb (44-22-son, NJ, USA) as described previously. 9 After 72 h of incu-1).…”

“…Negative controls (day 0 data) or without mature T cells (control) as described prewere examined using irradiated mice which had not viously. [10][11][12][13] Figure 1 shows sequential changes of BW of received transplants. Data shown are the mean of triple three kinds of chimeras after BMT and compares the results cultures.…”

“…8,9 It seemed that mismatch at the Mls-1 locus However, BMT mice prepared with a combination of both class I and non-MHC Ag mismatches showed signs between donors and recipients resulted in significant modification of acute GVHR. [10][11][12][13][14][15][16] We report different immunoof clinical GVHR and various cytokines were produced by the spleen cells at an early stage (4 days) after BMT.logical characteristics seen among donor T cells from various BMT chimeras where MHC and/or minor Ag are Although no clinical GVHR was detected in BMT chimeras prepared with a non-MHC mismatched but MHC matched or mismatched. The Mls-1 disparity significantly modified T cell responses and augmented or altered the matched combination, large amounts of various cytokines were secreted by spleen cells.…”