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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.

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


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.


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

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