骨髓间充质干细胞通过调节树突状细胞自噬改善哮喘的机制研究

Dendritic cells(DCs)，driving T cell-mediated immune responseas, play important role in initiation and progression of asthma.Deeper studies on the function of DCs in asthma will give us better understanding of the disease, hence benefit future potential therapeutic stratagy.Our preliminary data showed that transfusion of BMMSCs alleviates asthma and regulats functions of DCs.Besides,Autophagy can activate DCs functions, the downreglation of autophagy can inhibit DCs maturation and reduce its surface molecules and the expression of MHCⅡ.According to the genetic and histological evidence of autophagy in associated with asthma and asthma severity, autophagy affects the survival, proliferation and function of immune cells, especially the Th2 immune response,regulating autophagy may become a new choose for the treatment of asthma.So, we hypothessize that regulation of autophagy is the key change in BMMSCs conditioned DCs function.Autophagy downregulation leads to change in activity and chemotaxis of dendritic cells.To further characterize the role of autophagy in this model, we propose using Beclin-/-、Atg7flow/flow、CD11c Cre transgenic mice as our animal model. We will adopt multiple tenchniques including FACS, RT-PCR, Wertern blot,Immune electron microscopy and gene transfection to study the role of autophagy in BMMSCs conditioned DCs functions at transcription, translation and cellular levels. Hopefully we will adress the molecular mechanism underlying BMMSCs regulation of DCs functions by autophagy downregulation and provide experimental evidence for futher therapeutic stratagies.

树突状细胞（DCs）驱动的T细胞介导的免疫反应,在哮喘发生发展中起着重要作用，对DCs功能调节的深入研究有望突破目前哮喘治疗瓶颈。我们发现骨髓间充质干细胞（BMMSCs）可调节DCs功能及改善动物哮喘病情;另外自噬能活化DCs功能，阻断自噬能抑制DCs成熟并降低其表面共刺激分子和MHC-Ⅱ的表达。遗传和组织学证据表明，自噬参与哮喘发生并与哮喘严重程度相关，自噬影响免疫细胞的生存、增值和功能，特别是Th2免疫反应。故我们推测BMMSCs可通过下调DCs的自噬，以改变DCs的表型和功能，从而进一步改善哮喘的发生与发展。为进一步探索其机制，拟使用自噬基因敲除小鼠，通过流式分析、定量PCR、蛋白印迹、免疫电镜等手段，从转录、翻译、细胞活性等水平揭示自噬及DCs的自噬在BMMSCs改善哮喘发生发展中发挥的作用，为BMMSCs治疗哮喘提供新的证据，也为哮喘的靶向治疗提供新的思路。

遗传和组织学证据表明，自噬参与哮喘发生并与哮喘严重程度相关，树突状细胞(DCs)驱动的T细胞介导的Th2免疫反应,在哮喘发生发展中起着重要作用，自噬影响免疫细胞的生存、增殖和功能，特别是Th2免疫反应。对DCs 功能调节的深入研究有望突破目前哮喘治疗瓶颈。通过体内外实验，结果显示骨髓间充质干细胞(BMMSCs)可通过调节DCs功能及改善动物哮喘病情;另外自噬能活化DCs功能，阻断自噬能抑制DCs成熟并降低其表 面共刺激分子和MHC-II的表达。自噬及肺内DCs的自噬在哮喘的发生以及BMMSCs改善哮喘发生发展中发挥重要作用，BMMSCs可通过下调肺内DCs的自噬，以改变DCs的表型和功能，从而进一步改善哮喘的发生与发展，自噬抑制剂氯喹能通过抑制小鼠自噬水平，改善哮喘小鼠的免疫炎症反应。我们的研究为BMMSCs治疗哮喘提供新的证据，也为哮喘的靶向治疗提供新的思路。

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