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Title: Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by dimethyl fumarate
Authors: Han, J
Ma, S
Gong, H
Liu, S
Lei, L
Hu, B
Xu, Y
Liu, H 
Wu, D
Keywords: antioxidant
fumaric acid dimethyl ester
glutathione transferase alpha
heme oxygenase 1
programmed death 1 receptor
acute graft versus host disease
animal cell
animal experiment
animal model
antioxidant activity
bone marrow transplantation
CD25+ T lymphocyte
CD3+ T lymphocyte
CD4+ T lymphocyte
cell differentiation
cell proliferation
controlled study
cytotoxicity assay
enzyme linked immunosorbent assay
flow cytometry
gene expression
gene expression regulation
graft recipient
graft versus tumor effect
immune response
immunofluorescence microscopy
immunofluorescence test
mixed lymphocyte reaction
real time polymerase chain reaction
regulatory T lymphocyte
T cell depletion
T lymphocyte
Issue Date: 2017
Citation: Han, J, Ma, S, Gong, H, Liu, S, Lei, L, Hu, B, Xu, Y, Liu, H, Wu, D (2017). Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by dimethyl fumarate. Frontiers in Immunology 8 (NOV) : 1605. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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-a1 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-? 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. © 2017 Han, Ma, Gong, Liu, Lei, Hu, Xu, Liu and Wu.
Source Title: Frontiers in Immunology
ISSN: 16643224
DOI: 10.3389/fimmu.2017.01605
Rights: Attribution 4.0 International
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