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Front Immunol. 2017 Nov 20;8:1605. doi: 10.3389/fimmu.2017.01605. eCollection 2017.

Inhibition of Acute Graft-versus-Host Disease with Retention of Graft-versus-Tumor Effects by Dimethyl Fumarate.

Han J1,2,3, Ma S1,3, Gong H1, Liu S2,3, Lei L1,2,3, Hu B1,3, Xu Y1,2,3, Liu H4, Wu D1,2,3.

Author information

1
Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China.
2
Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
3
Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
4
Immunology Programme, Department of Microbiology and Immunology, Life Sciences Institute, National University of Singapore, Singapore, Singapore.

Abstract

Acute graft-versus-host disease (aGVHD) remains a clinical challenge and a major source of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dimethyl fumarate (DMF), an activator of Nrf2, has been shown to have anti-inflammatory and immunomodulatory properties without significant immunosuppression. We therefore hypothesized that DMF could be potentially harnessed for the treatment of aGVHD with retention of graft-versus-tumor effect. In this study, we showed that DMF significantly inhibited alloreactive T cell responses in vitro in mixed lymphocyte reaction assay. Administration of DMF significantly alleviated the severity, histological damage, and the overall mortality of aGVHD in an MHC-mismatched aGVHD model. DMF administration reduced the activation and effector function of donor T cells in vitro and in vivo. In addition, DMF treatment upregulated antioxidant enzymes heme oxygenase-1 and glutathione S-transferase-α1 expressions. Furthermore, DMF treatment markedly increased the frequencies of Treg cells. Depletion of CD25+ cells in DMF recipients aggravated aGVHD mortality compared with IgG control recipients. DMF could promote Treg cell differentiation in a dose dependent manner by upregulating TGF-β expression in vitro. Most importantly, DMF administration preserved graft-versus-leukemia effect after bone marrow transplantation. In conclusion, our findings demonstrated DMF as a promising agent for the prevention of aGVHD after allo-HSCT.

KEYWORDS:

Nrf2; Treg cells; acute graft-versus-host disease; dimethyl fumarate; graft-versus-leukemia

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