2017年11月20日，免疫学权威期刊Frontiers in Immunology（影响因子: 6.423）以研究论文形式发表了我院吴德沛教授、刘海燕教授研究团队关于急性移植物抗宿主病（aGVHD）的最新研究成果“Inhibition of Acute Graft-versus-Host Disease with Retention of Graft versus-Tumor Effects by Dimethyl Fumarate”。富马酸二甲酯（Dimethyl Fumarate，DMF）是Nrf2的靶向激动剂，能够激活Nrf2-ARE抗氧化信号通路，从而减轻活性氧对细胞的损害。其口服制剂Tecfidera能够显著降低多发性硬化症的残疾进程和复发率，于2013年被FDA批准作为一线药物用于治疗复发型多发性硬化症患者。DMF具有较好的免疫调节作用但是却没有明显的免疫抑制效应，提示其是治疗异基因造血干细胞移植后aGVHD非常有前景的药物。
在吴德沛教授和刘海燕教授的指导下，韩晶晶博士和马守宝博士在小鼠aGVHD模型中深入研究了DMF用于治疗aGVHD的作用及其机制。结果表明DMF能够抑制同种异体反应性T细胞应答，显著减轻小鼠aGVHD的病理进程，延长小鼠异基因造血干细胞移植后的总体生存率。机制研究表明DMF能够抑制供者T细胞的活化及效应功能，上调抗氧化酶血红素加氧酶-1和谷胱甘肽S-转移酶-α1，抑制氧化应激反应。进一步研究发现DMF能够通过上调TGF-β促进Treg细胞的增殖和分化，进而发挥抑制免疫应答的作用。此外，该研究也发现DMF在抑制aGVHD的同时能够保留移植物抗白血病作用。该项研究结果表明，DMF在预防和治疗aGVHD中具有广阔的应用前景。
原文摘要： 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.
