한빛사논문
Sena Kim 1, Sora Lim 1, Boram Kim 1, Julie Ritchey 2, Kiran Vij 3, Julie Prior 1, Lynne Marsala 4, Alyssa Stoner 1, Feng Gao 2, Samuel Achilefu 2, Matthew L Cooper 5, John F DiPersio 2, Jaebok Choi 6
1Washington University in St. Louis School of Medicine, Saint Louis, Missouri, United States.
2Washington University School of Medicine, St. Louis, Missouri, United States.
3Washington University School of Medicine.
4Washington University, St. Louis, Missouri, United States.
5Washington University School of Medicine, St Louis, United States.
6Washington Univ. School of Medicine, Saint Louis, Missouri, United States.
*Corresponding Author: Jaebok Choi
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GvHD) and malignant relapse limit its therapeutic success. We previously demonstrated that blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction of GvHD while preserving graft-versus-leukemia (GvL) effects. Nonetheless, the underlying molecular mechanisms remain inconclusive. In this study, we find that S100A9 is a novel GvHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduce GvHD without compromising GvL, altering donor T cell trafficking to GvHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improves GvHD in our mouse model of xenogeneic human PBMC transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab also reduces human T cell trafficking to GvHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GvHD suppressor without compromising GvL.
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