烟草暴露下的树突状细胞对T细胞向Th17分化的影响

Cigarette smoke is an important factor for COPD inflammation,dendritic cells(DCs) play a key role in presenting antigen and inducing T-cells differentiation. Th17 participate the inflammatory process of COPD. Whereas the effect of cigarette smoke on DCs and their impact on T cells differentiation is unclear. We demonstrated that Th17 expression had increased in the lung parenchyma of mice and erythromycin could regulate the regulatory T cell imblance in lung tissue induced by cigarette smoke in our previous research. So based these researches, we further investigate the effect of cigarette smoke induced DC on T cells differentiation:Firstly we observe the effect of cigarette smoke on Dcs functional status via detection of synthesis of aldehyde dehydrogenase(ALDH),IL-6 and IL-1. Secondly we investigate the he effect of cigarette smoke induced DC on differentiation from T cell differention to Th17,meanwhile we observe the effect of specific activator ALDH and the erythromycin on this process.This research will further recognize the mechanism of immune imblance in COPD,and provide the new target for treatment of COPD.

烟草烟雾暴露是COPD炎症的首要致病因素，树突状细胞（DCs）在抗原呈递诱导T细胞分化中起关键作用，Th17参与COPD炎症发病过程，然而烟草烟雾对DCs诱导T细胞向Th17分化的作用及机制尚无研究。我们前期研究发现Th17细胞在烟草烟雾暴露小鼠肺实质中增多并与炎症相关，且证实红霉素可调控烟草刺激下肺组织中调节性T细胞失衡。故本项目在前期研究的基础上进一步探讨烟草烟雾提取物(CSE)刺激下DC对T细胞分化的影响，首先探讨烟草烟雾下DCs醛脱氢酶和IL-1及IL-6的表达和功能状态，进而观察CSE刺激下DC细胞对T细胞分化成Th17的影响，同时观察特异性醛脱氢酶诱导剂以及红霉素对此过程的调节作用。以上研究为本课题的特色与创新点，研究的开展将有助于深化认识COPD中炎症与免疫失衡的机制以及寻找新的治疗靶点。

烟草烟雾暴露是COPD炎症的首要致病因素，获得性免疫反应的启动是COPD炎症放大与持续存在的重要机制。树突状细胞（DCs)是一种专职抗原提呈细胞，其在诱导T细胞分化中起关键作用。本课题研究围绕烟草烟雾暴露－树突状细胞活化（共刺激分子如CD40,CD86表达增加）－TH17细胞分化关系变化展开，探讨了烟草暴露下的树突状细胞诱导T细胞向TH17分化的相关分子机制及红霉素干预的作用。结果显示：1.烟草烟雾暴露可促进小鼠骨髓来源的mDC成熟（CD40,CD80,MHCII表达上调），并诱导CD4+T细胞向TH17细胞分化。2.红霉素可下调烟草烟雾暴露导致的mDC的MHCII和共刺激分子CD40,CD80,CD86的表达，从而阻止树突状细胞诱导TH17分化。3.阻断CD40/CD40L通路可以阻断烟草烟雾暴露下树突状细胞诱导TH17分化。本实验阐明了树突状细胞在COPD获得性免疫反应启动的作用。此外，说明了CD40/CD40L信号通路在烟草烟雾暴露下树突状细胞诱导TH17分化的重要作用，为后期进行CD40基因敲除小鼠的研究提供一定的理论基础，同时为COPD的防治提供可能的有效的靶点和药物。