IFN-γ通过调控DC分泌的IL-27抑制过敏性哮喘中Th9反应的研究

The mechanism of asthma is now not quite clearly and the effective therapy still need to explore. It has been found that IFN-γ and IL-27 can limit the airway inflammation of animal model of asthma. We suppose that IFN-γ may limit Th9-mediated airway inflammation in allergic asthma through dendritic cell modulation of IL-27. In order to explore the modulation of IFN-γ on DCs derived IL-27 and clarify the precise mechanism of IFN-γ and IL-27 in regulating the function of Th9 and then influence the airway inflammation of asthma, we will first clarify the expression and distribution of IL-27 and the receptor IL-27R in asthma and the cell sources of IL-27; second, we will investigate the directly effects of IFN-γ on Th9 differentiation and modulating the secretion of IL-27 from DCs in vitro and the expression and activation of transcription factors; third, DO11.10 mice derived naïve CD4+T cells were differentiated in vitro and stimulated with IL-27 which was derived from DCs stimulated by of IFN-γ, and then transferred into Rag2-/- mice and stimulated with OVA. We will investigate the airway inflammation, pathology and the level of IgE in serum; at last, the effects of IFN-γ on modulating the secretion of IL-27 from DCs and Th9 differentiation and airway inflammation of allergic asthma was detected by IFN-γ gene knock out animal models. In a word, we will demonstrate the real exactly regulation mechanism that the effects of IFN-γ-Th9 response or IFN-γ-DCs-IL-27-Th9 axis on allergic asthma in order to explore a new way for the therapy of allergic asthma.

哮喘发病机制尚未完全阐明，治疗尚需进一步探索。研究表明IFN-γ和IL-27可抑制哮喘小鼠模型的炎症，我们推测IFN-γ可直接或通过调控DC分泌的IL-27抑制过敏性哮喘中的Th9反应，进而抑制炎症。为明确具体机制，我们拟：①明确IL-27及其受体在哮喘的表达、分布、细胞来源；②研究IFN-γ对Th9分化的直接调控和对DCs分泌的IL-27的调控；③利用体外分化和过继转移Th9细胞的方法体内研究IFN-γ刺激DCs来源的IL-27对Th9分化的调控和关键转录因子的活化情况以及对哮喘炎症的影响；④体内研究探讨IFN-γ功能缺失对DCs分泌的IL-27的影响以及对Th9分化和哮喘炎症程度的影响。本研究立图明确IFN-γ-Th9反应或IFN-γ-DCs-IL-27-Th9细胞轴对过敏性哮喘调控作用及机制，为哮喘的治疗挖掘新途径并提供新的理论依据。