Anaphylatoxin regulation of the IL-33-ILC2 axis

 描述(申请人提供)：全球过敏性呼吸道疾病(哮喘、鼻炎、鼻窦炎等)的流行情况在过去的几十年里一直在不断上升。尽管有这些统计数据，但在过敏性疾病的根源上，驱动异常Th2免疫反应的过程仍有许多未知之处。更好地了解导致这些异常Th2免疫反应的机制将为开发新的治疗方法提供新的途径。最近的证据表明，细胞因子IL-33及其受体ST2对调节异常的Th2反应有深远的影响，并且在变态反应性疾病中显著失调，但知之甚少。 关于他们的规定。先天免疫介质已被证明在调节Th2反应中起中心作用，我们以前的工作已经证明补体途径在调节肺部异常的2型反应中起着中心作用。利用Th2过敏性气道炎的小鼠模型，我们提供了过敏性毒素(C3a和C5a)调节对变应原的过敏反应的证据，并在调节IL-33的产生上有直接作用。IL-33-ST2途径已被证明通过其在一种新描述的淋巴样细胞类型(固有淋巴样细胞-ILC)的发展中的中心作用来驱动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产生IL-33，以及通过直接接触ILC来控制其产生IL-13及其作为抗原提呈细胞(APC)的作用。提出了三个特定的目标，以促进我们对过敏性毒素对IL-33-ILC2轴的调节的理解。具体目的1将加深我们对过敏原诱导的IL-33中过敏毒素调节的理解。具体目标2将确定ILCs上的过敏毒素信号在调节IL-13产生中的作用。特定的 目的3将直接测试过敏毒素信号在集体调节ILC APC活性中的作用，本申请中提出的研究将使我们超越目前对先天2型反应如何发展的理解。我们的研究将开始描述补体途径在平衡肺内先天2型反应结果方面的中心作用。更好地了解这些新的途径将使我们能够确定新的治疗靶点，用于治疗目前治疗效果不佳的肺2型反应障碍患者。

 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.