CD4+ Treg细胞的PD-1表达调控肠缺血再灌后肠免疫屏障损伤的机制研究
结题报告
批准号:
81701874
项目类别:
青年科学基金项目
资助金额:
19.0 万元
负责人:
刘紫锰
依托单位:
学科分类:
H1602.器官功能衰竭与支持
结题年份:
2020
批准年份:
2017
项目状态:
已结题
项目参与者:
张旭宇、李云胜、张鹄菲、江智毅、司向、邱春芳、裴飞
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
客服二维码
微信扫码咨询
中文摘要
肠缺血再灌注(I/R)常导致危重患者的死亡。肠道免疫屏障破坏是肠I/R损伤的核心环节,但其机制尚不清楚。CD4+调节性T细胞(Treg)是调节免疫和炎症反应的关键细胞。既往我们发现肠缺血后肠内CD4+ T细胞的程序性死亡受体1(PD-1)表达降低,PD-1受抑被证实干扰了Treg细胞的功能和生成。我们的预实验首次发现肠I/R后激活PD-1可增加CD4+ Treg细胞数量并促进白介素(IL)-10和转化生长因子(TGF)-β1的生成,改善免疫球蛋白A的分泌。因此,我们假设肠I/R后PD-1的下调引起CD4+ Treg细胞生成IL-10和TGF-β1减少,造成肠道粘膜免疫反应障碍和淋巴细胞死亡,进而破坏了肠道免疫屏障。本项目拟使用Treg细胞诱导和基因干预等技术,探索肠I/R后CD4+ Treg细胞PD-1下调对肠道免疫屏障的影响及其分子机制,以期深入阐明肠I/R损伤的机制并寻找新的防治靶点。
英文摘要
Ischemia/reperfusion (I/R) injury of the intestine is associated with high morbidity and mortality in surgical and traumatic patients. Intestinal I/R injury leads to the destruction of intestinal mucosal barrier and subsequently multiple organ dysfunction syndrome. However, the mechanism of intestinal I/R-induced barrier injury is poorly understood. It has been demonstrated that CD4+ regulatory T cell (Treg) plays an important role in maintaining immune and inflammatory responses by regulating transforming growth factor (TGF)-β and interleukin (IL)-10 production. Our previous study demonstrated that, in peyer’s patches, the expression of programmed cell death-1 (PD-1) on CD4+ T cells significantly decreased following intestinal I/R. And the decreased PD-1 expression contributes to the death and dysfunction of Treg cell. The results of our preliminary experiment showed that, following intestinal I/R, activation of PD-1 promoted the number of CD4+ Treg cell and increased the production of TGF-β1 and IL-10, and then improved the intestinal immunoglobulin A synthesis. Therefore, we hypothesized that down-regulation of PD-1 may hinder the secretion of TGF-β1 and IL-10 from CD4+ Treg, lead to the death of lymphocytes and the disrupted mucosal immune responses in the intestine, and subsequently impair gut immune barrier after intestinal I/R injury. In this study, through using the techniques of Treg induction and gene knockout, we plan to investigate the effect of decreased PD-1 expression of CD4+ Treg cells on gut mucosal immunity after intestinal I/R, and elucidate the molecular mechanism of I/R-induced gut barrier injury. The data of this study will demonstrate the pathogenesis of intestinal I/R injury and provide new therapeutic targets for protecting gut mucosal immune barrier.
背景: CD4+调节性T细胞(Treg)是调节免疫和炎症反应的关键细胞。既往发现肠缺血后肠内CD4+T细胞的程序性死亡受体1(PD-1)表达降低,PD-1受抑被证实干扰了Treg细胞的功能和生成。我们的预实验首次发现肠I/R后激活PD-1可增加CD4+Treg细胞数量并促进白介素(IL)-10的生成,改善免疫球蛋白A的分泌。因此,我们假设肠I/R后PD-1的下调引起CD4+Treg细胞功能丧失,IL-10减少造成肠道粘膜免疫反应障碍和淋巴细胞死亡,破坏了肠道免疫屏障。研究内容: 1. 构建小鼠肠缺血(IR)模型,实验小鼠分为6组,分别为对照组(假手术组),肠I/R组,PD-L1 Ig 组 (PD-L1); 对照 IgG 组 ;PD-L1 Ig + Anti-IL-10 组;PD-L1 Ig+ MiR-155 agomir 组。检测指标:肠道PP结中CD4+细胞 PD-1 expression, IL-10 mRNA, IL-10表达;肠粘膜组织中的 miR-155 水平, (TNF)-α,IL-1β 浓度, 和AID的表达;肠道灌洗液中IgA 的细菌结合能力。2.使用野生型雄性C57/BL6小鼠和PD-1基因敲除小鼠构建肠IR模型,每组中均分别给予PD1阻断及IL-10中和,检测指标: 肠内IgA细菌结合能力、肠内菌群高通量、肠内细菌移位免疫荧光、远隔器官病理、生存分析。.重要结果:激活PD-1改善肠IR后IgA和IgM的抗菌能力,减轻肠IR后肠PP内炎症反应;激活PD-1通过CD4+T细胞/IL-10/miR-155信号轴调控肠IR后AID表达;PD-1阻断治疗造成肠道菌群紊乱、加重肠IR后肠、肝、肾损伤;PD-1基因敲除小鼠IL-10+Treg和Tfh较野生型小鼠增加。PD-1抗体处理组和PD-1基因敲除组小鼠肠PP和脾脏Treg细胞IL-10 mRNA表达均较对照组明显增加,PP和血清内IL-10含量亦升高。.结论及科学意义:肠道 CD4+T 细胞PD-1 激活可通过 IL-10/miR-155途径调控肠IR后肠道粘膜 IgA 生成和炎症反应,从而减少肠道免疫防御功能破坏。阻断PD-1信号通路可造成肠道菌群失调,并且加重肠IR后多器官损伤。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Terlipressin relieves intestinal and renal injuries induced by acute mesenteric ischemia via PI3K/Akt pathway.
特利加压素通过 PI3K/Akt 通路减轻急性肠系膜缺血所致肠肾损伤
DOI:10.7150/ijms.46302
发表时间:2020
期刊:International journal of medical sciences
影响因子:3.6
作者:Liu ZM;Lai HJ;Guan XD;Wen SH;Shen JT;Nie Y;Liu N;Zhang XY
通讯作者:Zhang XY
Activation of PD-1 Protects Intestinal Immune Defense Through IL-10/miR-155 Pathway After Intestinal Ischemia Reperfusion
肠道缺血再灌注后 PD-1 的激活通过 IL-10/miR-155 途径保护肠道免疫防御
DOI:10.1007/s10620-018-5282-2
发表时间:2018-09
期刊:Digestive Diseases and Sciences
影响因子:3.1
作者:Zhang Xu-Yu;Guan Su;Zhang Hu-Fei;Li Rui-Yun;Liu Zi-Meng
通讯作者:Liu Zi-Meng
高选择性V1受体激动剂特利加压素改善脓毒症相关急性肾损伤的机制研究
  • 批准号:
    --
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2019
  • 负责人:
    刘紫锰
  • 依托单位:
国内基金
海外基金