靶向组蛋白去甲基化转移酶Jmjd3调控耐受型DC分化干预GVHD新策略研究

Graft-versus-Host Disease (GVHD) is the major barrier for successful bone marrow/allogeneic hematopoietic stem cell transplantation. Dendritic cell (DC)-regulated immue balance plays a key role in maintaining the homeostasis. And DC-indcued T cell response is a key event in the pathogenesis f GVHD. The scientific problem of this project is the new strategy of targeting histone demethyltransferase Jmjd3 to regulate the differentiation and function of DC and then prevent and treat GVHD. Our preliminary results showed that Jmjd3 was highly expressed in DC derived from spleens of the GVHD mice, and its inhibitor GSK-J4 treatment could induce an increase in the number of tolerogenic DCs, leading to the increase in frequency of tolerogenic DCs/inflammatory DCs and alleviate GVHD. Our project intends to reveal that Jmjd3 promotes the differentiation of inflammatory DCs and inhibits their differentiation into tolerogenic DCs. Using GSK-J4, anti-RAGE neutralizing antibody, and tolerogenic DCs adoptive transfer, we expect to explore the cellular and molecular echanisms GSK-J4 takes to promote the differentiation of tolerogenic DCs and induce the transdifferentiation of tolerogenic DCs, and then finally regulate the T cell response, contributing to the alleviation of GVHD. Our study will clarify the pathogenesis of GVHD and provide novel theoretical and technical basis for GVHD inhibition by epigenetic regulation of immune balance, with Jmjd3 as the key target.

移植物抗宿主病（GVHD）是骨髓/造血干细胞移植临床应用的主要制限因素，树突状细胞（DC）调控的免疫平衡是维持机体稳态的关键。DC诱导的致病T细胞反应是GVHD病理机制的中心事件。本项目聚焦的科学问题是干预组蛋白去甲基化转移酶Jmjd3调控DC分化及功能防治GVHD的新策略。我们预初实验发现，GVHD小鼠脾脏DC的Jmjd3高表达，Jmjd3抑制剂GSK-J4处理可增加受鼠体内耐受型DC，使受鼠体内耐受型DC/炎症型DC比例上调并有效缓解GVHD。本项目拟研究和明晰Jmjd3通过调控RAGE信号促进炎症型DC的分化并抑制其向耐受型DC分化的作用；采用GSK-J4、抗RAGE中和抗体及耐受型DC过继转移等手段，揭示GSK-J4促进耐受型DC分化和诱导炎症型DC向耐受型DC转分化，并通过调控T细胞反应缓解GVHD的作用机制；建立以Jmjd3为核心靶标，表观调控干预免疫应答防治GVHD的新策略。

本项目按照计划书执行，已达到预期目标。我们利用Jmjd3抑制剂GSK-J4干预GVHD模型，发现GVHD发病过程中组蛋白去甲基化酶Jmjd3表达升高，抑制Jmjd3能够有效防治小鼠GHVD发病的严重程度并提高GVHD小鼠的生存率，靶向抑制Jmjd3能够介导炎症型DC比例下降而耐受型DC比例上升。进一步分析GVHD中Jmjd3对DC分化与功能的影响，发现靶向抑制Jmjd3可抑制DC对抗原的吞噬作用，抑制DC炎性细胞因子的分泌，且使DC刺激MLR的能力减弱，干预RAGE信号通路发现，Jmjd3抑制剂GSK-J4是通过调控RAGE信号缓解小鼠GVHD发病并提高GVHD小鼠的生存率。此外，我们利用Jmjd3抑制剂GSK-J4干预BMF模型，发现抑制Jmjd3能够抑制BMF小鼠体内异体反应性T细胞的免疫应答，但对BMF小鼠生存率的提升作用有限，而GSK-J4与MDSC联合治疗能显著提高对BMF的防治作用。由此可见，该研究以组蛋白甲基化修饰调控为切入点，探索Jmjd3在GVHD发生发展中的作用及机制，不但有助于解决GVHD发病机制及防治机理的相关基础理论问题，且有助于发现新的GVHD治疗靶点和干预途径。发表标注SCI论文2篇，另有1篇SCI论文处于修回状态，培养博士研究生3名。