Deaprtment of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, Tokyo, Japan.
PLoS One. 2018 Oct 11;13(10):e0203742. doi: 10.1371/journal.pone.0203742. eCollection 2018.
Chronic graft-versus-host disease (cGVHD) is a marked complication of hematopoietic stem cell transplantation, and multiple organs can be affected by cGVHD-induced inflammation and fibrosis. In clinical settings, immunosuppressive agents have been the last resort to treat cGVHD. However, it has been only partially effective for cGVHD. Hence, efficacious treatment of cGVHD is eagerly awaited. Our previous work suggested that oxidative stress was elevated in cGVHD-disordered lacrimal glands and that epithelial-to-mesenchymal transition (EMT) was implicated in fibrosis caused by ocular cGVHD. In addition, our recent article demonstrated that thioredoxin interaction protein (TXNIP) and transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-𝛋B) were associated with the development of cGVHD. After our search for effective drugs, we chose tranilast to combat systemic cGVHD. Tranilast is known to (1) act as an inhibitor of the inflammatory molecules TXNIP and NF-κB and (2) exert anti-fibrotic, anti-EMT and anti-oxidative effects. To investigate the effectiveness of tranilast for cGVHD, we used an MHC-compatible, multiple minor histocompatibility antigen-mismatched murine model of cGVHD. Tranilast or a solvent-vehicle were orally given to the allogeneic bone marrow transplantation (allo-BMT) recipients from the day before allo-BMT (Day-1) to Day 27 after allo-BMT. Their cGVHD-vulnerable organs were collected Day 28 after allo-BMT and analyzed by using various methods such as histology, immunohistochemistry and immunoblotting. As indicated by our results, tranilast alleviated cGVHD-elicited inflammation and fibrosis by suppressing the expression and/or activation of TXNIP and NF-κB and preventing EMT. Taken together, although this strategy may not be a complete cure for cGVHD, tranilast could be a promising medication to ameliorate cGVHD-triggered disabling symptoms.
慢性移植物抗宿主病 (cGVHD) 是造血干细胞移植的一种显著并发症，多个器官可能受到 cGVHD 诱导的炎症和纤维化的影响。在临床环境中，免疫抑制剂一直是治疗 cGVHD 的最后手段。然而，它们对 cGVHD 的治疗效果仅部分有效。因此，人们迫切期待有效的 cGVHD 治疗方法。我们之前的工作表明，氧化应激在 cGVHD 紊乱的泪腺中升高，上皮间质转化 (EMT) 与眼部 cGVHD 引起的纤维化有关。此外，我们最近的文章表明，硫氧还蛋白相互作用蛋白 (TXNIP) 和转录因子核因子 kappa-轻链增强子的 B 细胞 (NF-κB) 与 cGVHD 的发展有关。在寻找有效药物后，我们选择曲尼司特来对抗系统性 cGVHD。曲尼司特已知：(1) 作为炎症分子 TXNIP 和 NF-κB 的抑制剂；(2) 发挥抗纤维化、抗 EMT 和抗氧化作用。为了研究曲尼司特治疗 cGVHD 的效果，我们使用了一种 MHC 相容、多个次要组织相容性抗原不匹配的小鼠 cGVHD 模型。从异基因骨髓移植 (allo-BMT) 前一天 (第-1 天) 至 allo-BMT 后第 27 天，曲尼司特或溶剂载体通过口服给予 allo-BMT 受者。allo-BMT 后第 28 天收集 cGVHD 易损器官，并通过组织学、免疫组织化学和免疫印迹等多种方法进行分析。结果表明，曲尼司特通过抑制 TXNIP 和 NF-κB 的表达和/或激活以及防止 EMT，缓解了 cGVHD 引起的炎症和纤维化。总之，尽管这种策略可能不是 cGVHD 的完全治愈方法，但曲尼司特可能是改善 cGVHD 引起的致残症状的一种有前途的药物。
