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

Yan Liu, Christopher Bailey, Christopher Lazarski, Chun-shu Wong, Pan Zheng, Yang Liu, Yin Wang
doi: https://doi.org/10.1101/108951
Yan Liu
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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Christopher Bailey
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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Christopher Lazarski
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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Chun-shu Wong
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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Pan Zheng
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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Yang Liu
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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  • For correspondence: yaliu@cnmc.org ywang@cnmc.org
Yin Wang
Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Department of Pediatrics George, Washington University School of Medicine Washington, DC 20010, USA
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  • For correspondence: yaliu@cnmc.org ywang@cnmc.org
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Abstract

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 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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Posted February 16, 2017.
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Treatment of Graft-versus-Host Disease by Echinomycin in a New Humanized Mouse Model
Yan Liu, Christopher Bailey, Christopher Lazarski, Chun-shu Wong, Pan Zheng, Yang Liu, Yin Wang
bioRxiv 108951; doi: https://doi.org/10.1101/108951
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Treatment of Graft-versus-Host Disease by Echinomycin in a New Humanized Mouse Model
Yan Liu, Christopher Bailey, Christopher Lazarski, Chun-shu Wong, Pan Zheng, Yang Liu, Yin Wang
bioRxiv 108951; doi: https://doi.org/10.1101/108951

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