FGN通过调节肥大细胞活性提高呼吸道过敏性疾病免疫治疗的疗效及其机制研究

Allergic airway disease (AAD) has become a serious problem of human health. The pathological characteristics of AAD are Th2 dominance and immune intolerance. At present, the therapeutic effect of AAD is not satisfactory. Specific immunotherapy is the countermeasure of AAD, but the therapeutic efficacy needs to be improved. Mast cells (MC) are the main effector cells of AAD. In addition to releasing allergic mediators, MC also releases IL-4, which plays an important role in triggering Th2 dominance and inhibiting regulatory T cell (Treg) generation. In the preliminary studies, we observed that TLR5 agonist flagellin (FGN) could down-regulate the activity of sensitized MC and inhibit the expression of IL-4 in MC. MC activation significantly affected the initial differentiation of CD4+T cells into Treg. These data suggest that FGN may enhance the efficacy of AAD immunotherapy. The proposed study includes: to explore the role of FGN in regulating the expression of IL-4 in MC; to observe the effect of FGN on the induction of antigen-specific Treg in AAD immunotherapy; and to observe the inhibitory effect of FGN combined with immunotherapy on AAD. The expected results will further clarify the pathogenesis of AAD and provide a new and effective therapeutic remedy for AAD.

呼吸道过敏性疾病（AAD）已成为影响人类健康的重要问题。AAD的病理特点是Th2优势和免疫耐受失常。目前AAD的疗效不满意。特异性免疫治疗是AAD的对因治疗措施，但疗效有待改善。肥大细胞（MC）是AAD的主要效应细胞；除了释放过敏有关的介质之外，MC还释放IL-4，在触发Th2优势和抑制调节性T细胞（Treg）方面有重要作用。我们在前期研究中观察到鞭毛素（FGN）可以下调致敏MC的活性；抑制MC表达IL-4的功能。MC激活时显著影响初始CD4+T细胞分化成为Treg。这些资料提示FGN可能上调AAD免疫治疗的疗效；因此，我们在本项目中进一步研究：探讨FGN调节IL-4在MC中表达的作用；观察FGN在AAD免疫治疗中促进抗原特异性Treg的诱导；联合应用FGN和免疫治疗对AAD的抑制作用观察。预期结果将进一步明确AAD的发病机理；为AAD的治疗提供一种新的、有效的治疗方法。

呼吸道过敏性疾病（AAD）已成为影响人类健康的重要问题。AAD的病理特点是Th2优势和免疫耐受失常。目前AAD的疗效不满意。特异性免疫治疗是AAD的对因治疗措施，但疗效有待改善。肥大细胞（MC）是AAD的主要效应细胞；除了释放过敏有关的介质之外，MC还释放IL-4，在触发Th2优势和抑制调节性T细胞（Treg）方面有重要作用。我们在研究中观察到TLR5激动剂鞭毛素（FGN）可以下调致敏MC的活性，FGN 通过JAK/STAT3 信号通路抑制肥大细胞 IL-4 的转录活性与表达水平。在进一步的研究中，我们发现FGN 在 AAD 疾病免疫治疗中对抗原特异性 Treg 细胞的促进作用；并观察到 FGN 抑制呼吸道粘膜组织肥大细胞 IL-4 炎症因子的表达从而促进 AAD 疾病呼吸道 Treg 细胞的诱导。在利用基因敲除的小鼠Il4f/fCkit-Cre小鼠（以下简称Il4Ckit小鼠）中，进一步验证了我们以上的结论。为此，我们制备了FGN-OVA 融合蛋白，并且利用过敏性鼻炎小鼠的模型，发现FGN-OVA 融合蛋白能够通过诱导机体免疫耐受，提高AAD疾病的疗效。