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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 29

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

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

×

Figure 10

Preventative treatment with RTrx1 reduces GVHD in NSG xenograft mouse model.

Options: View larger image (or click on image) Download as PowerPoint
Preventative treatment with RTrx1 reduces GVHD in NSG xenograft mouse mo...
CFSE-labeled human T cells were stimulated with human T cell–depleted antigen-presenting cells isolated from an HLA-mismatched donor for 5 days in the presence or absence of 2 μg/ml RTrx1. Cells were subjected to FACS staining and analyzed for IFN-γ production. (A) Intracellular IFN-γ expression is shown on gated CD4+ or CD8+ cells. (B) The mean ± SD of IFN-γ+ cells is shown for CD4+ and CD8+ T cells, respectively. (C and D) In the same setting, cells were washed and stained with DCF-DA (C), and the MFI ± SD for DCF-DA+ CD4+ and CD8+ is shown, respectively (D). Data shown here are from 1 of 2 independent experiments. Significance was determined by Student’s t test. In separate experiments, NSG-A2+ mice were irradiated (250 cGy) and underwent transplantation with HLA-A2– human PBMCs (10 × 106 to 13 × 106). Recipient mice were injected with vehicle alone or with human RTrx1 at 5 μg/mouse/day from day –1 to day 14. (E and F) Recipients were monitored for clinical score (E) and survival (F) until 60 days after transplantation. Data shown here are from 2 combined experiments (n = 13–14 per group). 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. *P < 0.05, **P < 0.01, and ***P < 0.001.