共信号分子PD-1H快速控制化脓性角膜炎及免疫调控机制研究

The excessive inflammation mediated by neutrophils is a major contributor to the pathology during suppurative keratitis, yet current antibiotics treatment commenly does not reduce the high rate of blindness resulting from immunopathological processes. Previously, the novel co-signal molecule PD-1H was reported, characterized by a rapid modulation of early immune responses that controlled some acute inflammation models such as acute hepatitis as well as acute graft-versus-host disease, which is distinct from other co-signal molecules that mainly functions in acquired immunity. Consistent with its rapid modulation, PD-1H was found highly expressed on innate immune cells such as neutrophils. Furthermore, we discovered by preliminary experiments that PD-1H substantially blocked the augmented neutrophils during LPS-induced endotoxemia, indicating its potential powerful modulation of innate immunity. Based on the abundant preliminary studies, we for the first time proposed that PD-1H could control the excessive inflammation by inhibiting neutrophil infiltrating into cornea, preventing tissue injury and blindness. Our hypothesis-driven studies will be developed by both in vivo and in vitro researches aiming at clarifying the role of PD-1H in the modulation of neutrophil responses and the control of suppurative keratitis. Our long-term objective is to develop early therapeutic intervention to rapidly control suppurative keratitis and reduce its high rate of blindness.

中性粒细胞介导的过度炎症反应是化脓性角膜炎急剧进展的主要原因，现有的抗生素治疗并不能有效减少由于免疫病理损伤导致的高致盲率。前期已报道共信号分子家族新成员PD-1H，与既往所知的主导获得性免疫应答调控的其它共信号分子相比，作用更为迅速，能及时控制急性肝炎、急性移植物抗宿主病等急性炎症模型。进一步发现PD-1H呈高水平表达于中性粒细胞等天然免疫细胞上。近期我们预实验结果显示：PD-1H能大幅度阻断内毒素血症导致的中性粒细胞数量增加，提示着PD-1H对天然免疫系统可能具有较强的调节功能。由此，本项目提出“PD-1H通过抑制中性粒细胞浸润，及时控制过度炎症反应、避免角膜损伤致盲”的假说，拟从机体水平研究PD-1H如何控制化脓性角膜炎的免疫病理反应，从细胞水平分析PD-1H如何调控中性粒细胞介导的天然免疫反应，为寻找快速有效控制化脓性角膜炎、降低致盲率的新措施提供理论依据。

PD-1H是新近发现的共信号分子家族新成员，目前仅有的研究显示PD-1H负调控获得性免疫反应。本课题集中于PD-1H对天然免疫炎症的调控研究，建立无菌性炎症模型，研究PD-1H对模型动物生存率的影响，并从血清学和病理学角度分析PD-1H对重要器官功能的影响，通过分析外周血白细胞数量及分类，研究PD-1H对机体炎症状态的控制，通过体外细胞实验，研究PD-1H对天然免疫细胞状态和功能的影响。本课题从PD-1H基因敲除小鼠，抗PD-1H单克隆抗体和可溶性PD-1H融合蛋白的角度，全面分析了PD-1H在天然免疫炎症系统中的作用。本课题开启了共信号分子PD-1H在天然免疫领域的研究，为天然免疫炎症的调控和临床上脓毒症的控制提供新的突破口，并推动其它共信号家族成员在天然免疫中的研究进展。