Anaphylatoxin regulation of the IL-33-ILC2 axis

 描述（由申请人提供）：全球范围内，过敏性气道疾病（哮喘、鼻炎、鼻窦炎等）的患病率在过去的几十年里一直在持续上升。尽管有这些统计数据，但关于在过敏性病理学的根源处驱动异常Th 2免疫应答的过程仍有许多未知之处。更好地理解负责驱动这些异常的Th 2免疫应答的机制将为我们提供新的治疗方法的开发新的途径。最近的证据表明，细胞因子IL-33及其受体ST 2对调节异常的Th 2应答具有深远的影响，并且在变应性疾病中显著失调，但知之甚少 关于他们的规则。先天性免疫介质已被证明是调节Th 2应答的中心，我们以前的工作已经证明了补体途径在调节肺中异常的2型应答中的中心作用。利用小鼠Th 2过敏性气道炎症模型，我们提供了证据表明过敏毒素（C3 a和C5 a）调节对变应原的过敏反应，并对调节IL-33的产生有直接作用。IL-33-ST 2途径已被证明通过其在新描述的淋巴细胞类型（先天淋巴细胞-ILC）发育中的核心作用来驱动2型反应。我们的初步数据表明，补体通过多种非相互排斥的途径调节异常的2型反应：通过直接调节肺上皮细胞的IL-33产生，并通过直接参与ILC来控制其IL-13的产生及其作为抗原呈递细胞（APC）的作用。提出了三个具体的目标，以提高我们的理解的调节IL-33-ILC 2轴过敏毒素。特异性目的1将进一步加深我们对过敏毒素调节过敏原诱导的IL-33的理解。特异性目标2将确定过敏毒素信号传导在ILCs上调节IL-13产生的作用。具体 目的3将直接测试过敏毒素信号传导在调节ILC的APC活性中的作用。总的来说，本申请中提出的研究将使我们超越我们目前对先天2型应答如何发展的理解。我们的研究将开始表征补体途径在平衡肺中先天性2型反应结果中的中心作用。更好地了解这些新的途径将使我们能够确定新的治疗干预目标，用于治疗目前治疗不足的肺2型反应失调的个体。

 DESCRIPTION (provided by applicant): Worldwide, the prevalence of allergic airway diseases (asthma, rhinitis, sinusitis, etc.) has been continuously rising in the past decades. Despite these statistics, much remains unknown about the processes that drive the aberrant Th2 immune responses at the root of allergic pathologies. A greater understanding of the mechanisms responsible for driving these aberrant Th2 immune responses would provide us with novel pathways for the development of new treatment approaches. Recent evidence suggests that the cytokine IL-33, and its receptor, ST2, have profound effects on regulating aberrant Th2 responses, and are significantly dysregulated in allergic disease, yet little is known about their regulation. Innate immune mediators have been shown to be central in regulating Th2 responses, and our previous work has demonstrated a central role for the complement pathway in regulating aberrant type 2 responses in the lungs. Using mouse models of Th2 allergic airway inflammation, we provide evidence that the anaphylatoxins (C3a and C5a) regulate the allergic response to allergen, and have direct actions on regulating IL-33 production. The IL-33-ST2 pathway has been shown to drive type 2 responses through its central role in the development of a newly described lymphoid cell type (innate lymphoid cells-ILC). Our preliminary data suggests that complement regulates aberrant type 2 responses through multiple non-mutually exclusive pathways: by directly regulating IL-33 production from the lung epithelium and by directly engaging ILCs to control their production of IL-13 and their role as antigen-presenting cells (APCs). Three specific aims are proposed to advance our understanding of the regulation of the IL-33-ILC2 axis by anaphylatoxins. Specific Aim 1 will further our understanding of anaphylatoxin regulation of allergen- induced IL-33. Specific Aim 2 will determine the role of anaphylatoxin signaling on ILCs in regulating IL-13 production. Specific Aim 3 will directly test the role of anaphylatoxin signaling in modulating the APC activity of ILCs Collectively, the studies proposed in this application will move us beyond our current understanding of how type innate 2 responses develop. Our studies will begin to characterize the central role of the complement pathway in balancing the outcome of innate type 2 responses in the lungs. A better understanding of these novel pathways will enable us to identify new targets for therapeutic interventions in individuals with dysregulated lung type 2 responses that are underserved by current therapies.