移植物抗宿主病（GVHD）已成为异体骨髓/造血干细胞移植的主要限制因素，而异体效应型记忆CD8+ T细胞（TEM）是造成GVHD损伤的关键因素。近年研究表明表观修饰是调控免疫细胞活化、分化及效应功能的重要形式。项目组预初实验首先发现新型组蛋白去乙酰化酶抑制剂AR42可抑制受者体内TEM细胞，并有效缓解GVHD，这一效应也可能与AR42 调抑树突状细胞（DC）作用有关，提示组蛋白乙酰化/去乙酰化表观修饰可调控TEM，并是防治GVHD的有效途径。在此基础上，拟进一步研究组蛋白乙酰化/去乙酰化表观修饰对TEM细胞分化、增殖、稳态维持及效应功能的调控，阐释其与Wnt/TCF-1信号通路和/或DC刺激信号等有关的细胞和分子机制。以此揭示表观调控在GVHD发生发展中的作用及机制，建立以组蛋白乙酰化/去乙酰化表观修饰调控TEM细胞为手段的GVHD防治新策略。

Graft-versus-host disease (GVHD) is a major barrier for successful allogeneic hematopoietic stem cell transplantation. Allogeneic memory effector CD8+ T cells (TEM), which mediate host tissue injury, and dendritic cells, which initiate allogeneic T cell responses, play essential roles in the development of the disease. Epigenetic modification is known to be involved in the activation, differentiation and effector function of T cells. In the pilot study, we found for the first time that AR42, which is a specific histone deacetylase inhibitor, significantly decreased TEM and reduced GVHD in experimental mice. In addition, we found that treatment of dendritic cells with AR42 resulted in the generation of dendritic cells with enhanced suppressive effects on TEM. These findings suggest that modulation of TEM and dendritic cells by targeting histone acetylation and deactylation have beneficial effects on reducing GVHD. Building on these results, we propose to study the regulatory effects of histone acetylation and deactylation on differentiation, proliferation, homeostasis and effector function of TEM, dissect the relationships among histone acetylation and deactylation, Wnt signaling pathway, and activation of dendritic cells. Our study will provide new insights into the essential roles of histone acetylation and deactylation in the pathogenesis of GVHD and illuminate the underlying mechanisms. Results from these studies, if accomplished, will lead to new strategies to treat GVHD by epigenetic modulation of allogeneic T cell responses.