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* Hematology Branch, National Heart, Lung, and Blood Institute, and
Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD 20892
Human bone marrow (BM) failure mediated by the immune system can be modeled in mice. In the present study, infusion of lymph node (LN) cells from C57BL/6 mice into C.B10-H2b/LilMcd (C.B10) recipients that are mismatched at multiple minor histocompatibility Ags, including the immunodominant Ag H60, produced fatal aplastic anemia. Declining blood counts correlated with marked expansion and activation of CD8 T cells specific for the immunodominant minor histocompatibility Ag H60. Infusion of LN cells from H60-matched donors did not produce BM failure in C.B10 mice, whereas isolated H60-specific CTL were cytotoxic for normal C.B10 BM cells in vitro. Treatment with the immunosuppressive drug cyclosporine abolished H60-specific T cell expansion and rescued animals from fatal pancytopenia. The development of BM failure was associated with a significant increase in activated CD4+CD25+ T cells that did not express intracellular FoxP3, whereas inclusion of normal CD4+CD25+ regulatory T cells in combination with C57BL/6 LN cells aborted H60-specific T cell expansion and prevented BM destruction. Thus, a single minor histocompatibility Ag H60 mismatch can trigger an immune response leading to massive BM destruction. Immunosuppressive drug treatment or enhancement of regulatory T cell function abrogated this pathophysiology and protected animals from the development of BM failure.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Jichun Chen, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Clinical Research Center Room 3-5132, 10 Center Drive, Bethesda, MD 20892-1202. E-mail address: chenji{at}nhlbi.nih.gov
2 Abbreviations used in this paper: AA, aplastic anemia; BM, bone marrow; GVH, graft-vs-host; HSC, hemopoietic stem cell; LN, lymph node; minor H, minor histocompatibility; TBI, total body irradiation; Treg, regulatory T cell.
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