Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease

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Abstract

Oxidative stress is elevated in the recipients of allogeneic hematopoietic transplantation (allo-HCT) and likely contributes to the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production and migration of alloreactive donor T cells, and remains a major cause of morbidity and mortality after allo-HCT. Hence, strategies to limit oxidative stress in GVHD are highly desirable. Thioredoxin1 (Trx1) counteracts oxidative stress by scavenging reactive oxygen species (ROS) and regulating other enzymes that metabolize H2O2. The present study sought to elucidate the role of Trx1 in the pathophysiology of GVHD. Using murine and xenograft models of allogeneic bone marrow transplantation (allo-BMT) and genetic (human Trx1-transgenic, Trx1-Tg) as well as pharmacologic (human recombinant Trx1, RTrx1) strategies; we found that Trx1-Tg donor T cells or administration of the recipients with RTrx1 significantly reduced GVHD severity. Mechanistically, we observed RTrx1 reduced ROS accumulation and cytokine production of mouse and human T cells in response to alloantigen stimulation in vitro. In allo-BMT settings, we found that Trx1-Tg or RTrx1 decreased downstream signaling molecules including NFκB activation and T-bet expression, and reduced proliferation, IFN-γ production and ROS accumulation in donor T cells within GVHD target organs. More importantly, administration of RTrx1 did not impair the graft-versus-leukemia (GVL) effect. Taken together, the current work provides a strong rationale and demonstrates feasibility to target the ROS pathway, which can be readily translated into clinic.

Authors

M. Hanief Sofi, Yongxia Wu, Steven D. Schutt, Min Dai, Anusara Daenthanasanmak, Jessica Heinrichs Voss, Hung Nguyen, David Bastian, Supinya Iamsawat, Shanmugam Panneer Selvam, Chen Liu, Nilanjana Maulik, Besim Ogretmen, Junfei Jin, Shikhar Mehrotra, Xue-Zhong Yu