Drug development effort against GVHD is hampered by the lack of clinically relevant humanized animal models for preclinical testing. Current humanized GVHD models rely on adoptive transfer of a high number of human peripheral blood mononuclear cells (PBMCs) into immunodeficient mice. Here we report a novel humanized GVHD model by transplanting a small number of human BM cells into newborn NOD.SCID IL2rγ0 (NSG) mice. Transplantation of human BM cells (BMT) causes acute GVHD, with lethality between 15 to 60 days. Pervasive human T-cell infiltration into multiple organs, including lung, intestine, skin, kidney, liver, and stomach, was observed in all mice analyzed. Surprisingly, the human T cells express high levels of hypoxia inducible factor 1α (HIF1α) protein even under normoxic environment. Administration of Echinomycin, a potent inhibitor for HIF1α, rapidly ablated HIF1α protein in T cells and gradually reduced the frequency of human cells in the peripheral blood and target organs. Echinomycin provides a sustained therapeutic effect, as demonstrated by dramatic reduction of clinical symptoms, pathology score and by doubling of the median life span of the chimeric mice. Our results reveal a critical role of HIF1α in GVHD and demonstrate that HIF1α inhibitors such as Echinomycin should be explored for clinical drug development against GVHD.
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