Treatment of Graft-versus-Host Disease by Echinomycin in a New Humanized Mouse Model

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 IL2ry0 (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 1 (HIF1) protein even under normoxic environment. Administration of Echinomycin, a potent inhibitor for HIF1, rapidly ablated HIF1 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 HIF1 in GVHD and demonstrate that HIF1 inhibitors such as Echinomycin should be explored for clinical drug development against GVHD.