inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by dimethyl fumarate
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2017
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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.
| Reference Key |
han2017frontiersinhibition
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| Authors | ;Jingjing Han;Jingjing Han;Jingjing Han;Shoubao Ma;Shoubao Ma;Huanle Gong;Shuangzhu Liu;Shuangzhu Liu;Lei Lei;Lei Lei;Lei Lei;Bo Hu;Bo Hu;Yang Xu;Yang Xu;Yang Xu;Haiyan Liu;Depei Wu;Depei Wu;Depei Wu |
| Journal | sudebno-meditsinskaia ekspertiza |
| Year | 2017 |
| DOI |
10.3389/fimmu.2017.01605
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| URL | |
| Keywords |
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