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Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease
M. Hanief Sofi, … , Shikhar Mehrotra, Xue-Zhong Yu
M. Hanief Sofi, … , Shikhar Mehrotra, Xue-Zhong Yu
Published May 2, 2019
Citation Information: J Clin Invest. 2019;129(7):2760-2774. https://doi.org/10.1172/JCI122899.
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Research Article Immunology Article has an altmetric score of 29

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 cell 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. Thioredoxin-1 (Trx1) counteracts oxidative stress by scavenging 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-Tg) as well as pharmacological (human recombinant Trx1 [RTrx1]) strategies, we found that Trx1-Tg donor T cells or administration of RTrx1 to the recipients significantly reduced GVHD severity. Mechanistically, we observed that 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 NF-κB 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 effect. Taken together, the current work provides a strong rationale for, and demonstrates the feasibility of, targeting the ROS pathway, which can be readily translated to the 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

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Figure 6

Trx1 treatment reduces GVHD mortality by modulating T cell expansion and migration after allo-BMT.

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Trx1 treatment reduces GVHD mortality by modulating T cell expansion and...
BALB/c mice were lethally irradiated and underwent transplantation with 5 × 106 per mouse T cell–depleted bone marrow cells (TCD-BM, Ly5.1+) with or without purified T cells (Ly5.2+) (0.5 × 106 per mouse) from B6 mice. One group of recipient mice was injected with human RTrx1 at 5 μg/mouse/day from day –1 to day 14. (A and B) Recipients were monitored for survival and clinical score until 80 days after BMT (n = 10 per group). Data shown here are from 2 combined experiments. For comparison of recipient survival among groups, the log-rank test was used to determine statistical significance. Clinical scores were compared using a nonparametric Mann-Whitney U test. In separate experiments with the same setting, recipient spleens and livers were collected 2 weeks after BMT, and mononuclear cells were subjected to cell counting and FACS staining. (C and D) CD4 and CD8 expression is shown on gated donor cells among live spleen or liver cells. IFN-γ and Foxp3 expression is shown on gated donor CD4+ cells from a representative mouse from each group. (E–H) Percentage IFN-γ+ or Foxp3+ donor (H2Kb+Ly5.1–) CD4+ (E and G) and CD8+ cells (IFN-γ) (F and H) is summarized in recipient spleen and liver, respectively. (I) CXCR3 expression is shown on donor-derived (H2Kb+) CD4+ and CD8+ cells in 1 representative recipient. (J) Percentage CXCR3+ cells is summarized on donor-derived CD4+ and CD8+ in recipient spleen. The data are from 1 representative of 2 independent experiments. Significance was determined by Student’s t test. *P < 0.05, **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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