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.
Highlights
Allogeneic hematopoietic stem cell transplantation has become a potential curative treatment for malignant hematological diseases [1]
The results showed that Dimethyl fumarate (DMF) significantly inhibited the proliferation of alloreactive T cells in a dose-dependent manner on day 5 determined by 3H-TdR and CFSE dye dilution (Figures 1B,C)
To address whether DMF has a direct effect on T cells, we performed a T cell activation assay with anti-CD3/CD28 stimulation, the result showed that DMF could significantly inhibit T cells proliferation directly (Figure S1A in Supplementary Material)
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a potential curative treatment for malignant hematological diseases [1]. The success of an allo-HSCT is frequently limited by life-threatening complications, such as acute graft-versus-host disease (aGVHD) [1]. DMF Inhibits GVHD with Retention of GVL. They contribute to the initiation and development and of aGVHD, and have been considered as potential targets for the treatment and prevention of aGVHD [3]. Therapy of established aGVHD is still dependent on corticosteroids, despite their limited efficacy and considerable toxicity [2]. Development of novel therapies will be critical for the prevention and treatment of aGVHD
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