A mouse model of lymphocyte infusion-induced bone marrow failure.

Abstract

OBJECTIVE To develop a mouse model for the study of the pathophysiologic mechanism and treatment of human bone marrow (BM) failure. MATERIALS AND METHODS Unmanipulated B6D2F1 or CByB6F1 hybrid mice were infused with 10-40 x 10(6) lymph node (LN) cells from their C57BL/6 (B6) parent. Pancytopenia was monitored by cell counting, while marrow damage was assessed by histological staining. Destruction of BM hematopoietic progenitor/stem cells was measured by colony formation in vitro and irradiation protection in vivo. Serum interferon-gamma (IFN-gamma) concentration was measured by enzyme-linked immunosorbent assay. BM T cell Vbeta and Fas expressions were analyzed by flow cytometry. Treatment effects of immunosupressive agents cyclosporine, antithymocyte globulin (ATG), anti-IFN-gamma, and anti-tumor necrosis factor-alpha (anti-TNF-alpha) were tested. RESULTS Infusion of 30-40 x 10(6)B6 LN cells led to rapid development of severe pancytopenia, BM hypoplasia, and death. Affected mice had drastically reduced hematopoietic progenitor and stem cells. BM of affected mice showed lymphocyte infiltration, oligoclonal T cell expansion, and upregulated Fas expression. Serum IFN-gamma concentration increased two- to three-fold. Timed administration of cyclosporine or ATG abrogated pancytopenia. Treatment with anti-IFN-gamma antibody reliably rescued mice, and treatment with anti-TNF-alpha antibody extended animal survival significantly. CONCLUSION This mouse model indicates that activated lymphocytes and type I cytokines play important roles in marrow destruction in lymphocyte infusion-induced BM failure.

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