髓系衍生抑制性细胞调控肝硬化合并脓毒血症单核/巨噬细胞功能及相关机制研究

Cirrhotic patients are prone to sepsis upon bacterial infection , which lead to high mortality. Recent literatures and our previous study showed monocyte/macrophage hyper-activation contributed to excessive inflammatory response against bacterial infection in cirrhotic patients. Therefore, to curb over-activation of monocyte/macrophage is one of potential therapeutic targets for treating the disease. Recent studies revealed that a group of so-called myeloid derived suppressor cells (MDSCs) could inhibit inflammatory response of macrophage. And our preliminary study has shown a compensatory elevation of MDSCs in peripheral blood of cirrhotic patients. In this project, we measured MDSCs frequency and explored the factors affecting the MDSC differentiation and chemiotaxis in cirrhotic patients with sepsis and mice model. We then investigate the role of MDSCs in regulating antigen presentation, phagocytosis and cytokine production of monocyte/macrophage and the underlying mechanism. We also explore the potential therapeutic effect of adoptive transfer of MDSCs on cirrhotic mice with sepsis. The study would shed light on novel immunotherapy for cirrhotic patients with sepsis.

肝硬化患者合并细菌感染后容易进展为脓毒血症，导致较高的死亡率。最近资料及本项目组前期研究发现单核/巨噬细胞过度活化是导致肝硬化患者机体针对细菌感染的炎症反应过强的重要因素。因此如何抑制单核/巨噬细胞过度的炎症反应是阻断疾病进程的可能治疗靶点。最近研究提示一群称为髓系衍生抑制性细胞的细胞群可抑制巨噬细胞炎症应答，而我们在前期研究中发现，在肝硬化脓毒血症患者外周血中代偿性地升高。在本项目中，我们拟收集肝硬化脓毒血症患者外周血标本，同时利用肝硬化脓毒血症小鼠模型，分析肝硬化脓毒血症状态下的MDSC细胞的数量变化，探讨影响MDSC细胞分化及趋化的因素，研究MDSC细胞对单核/巨噬细胞抗原提呈、吞噬、细胞因子分泌等免疫功能的具体调控作用及相关机制，并研究过继回输MDSC治疗肝硬化脓毒血症的效果，为探索肝硬化脓毒血症治疗新方法提供理论依据。

重症肝病患者易发生细菌感染。细菌感染可导致肝衰竭，甚至多器官功能衰竭，增加死亡率。本课题组基于临床研究结果，探讨其可能机制，探讨髓系衍生抑制性细胞(myeloid derived suppressor cells, MDSCs)在内毒素+D-氨基半乳糖诱导的肝衰竭中的作用。我们发现MDSCs在肝衰竭小鼠骨髓、外周血、脾脏及肝脏内均有明显扩增， 但在骨髓中最为明显。MDSC从骨髓释放迁徙至炎症部位，可能由一系列趋化因子受体如CCR2、CX3CR1、CXCR2等介导，同时伴有表型的动态变化；进一步发现MDSC在骨髓释放迁徙至炎症部位过程中免疫抑制的功能逐渐减弱，而促炎能力不断增强。进一步发现这一过程可能与活化的NKT细胞有关，其能诱导MDSC在肝脏内的进一步分化，同时MDSC能够反馈性活化NKT，扩大炎症反应。由此，MDSCs在从骨髓释放，招募至炎症部位的过程中，其功能存在一动态演变，最终在炎症部位与NKT相互作用，导致炎症扩大，病情进展。该研究结果提供了一种潜在的重症肝病的细胞治疗方法。