Anaphylatoxin regulation of the IL-33-ILC2 axis

过敏毒素对 IL-33-ILC2 轴的调节

基本信息

批准号：
9232672
负责人：
Stephane Lajoie
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232672
关键词：
Address Allergens Allergic Allergic Disease Allergic inflammation Anaphylatoxins Antigen-Presenting Cells Asthma Automobile Driving Biological Response Modifiers Cell physiology Complement Complement 2 Complement 3a Complement 5a Data Development Disease Epithelial Epithelial Cells Epithelium Equilibrium Goals Health Healthcare Human Immune response Immunity Incidence Individual Inflammatory Response Interleukin-13 Knowledge Lead Lung Lung Inflammation Lymphoid Cell Mediating Modality Mucous Membrane Outcome Pathogenesis Pathology Pathway interactions Patients Plant Roots Prevalence Process Production Regulation Rhinitis Role Severities Signal Transduction Sinusitis TLR4 gene Testing Therapeutic Intervention Tissues Work allergic airway disease allergic airway inflammation allergic response cell type complement pathway cytokine in vivo mouse model novel novel therapeutics receptor response statistics

项目摘要

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.

描述（由申请人提供）：过去几十年来，全世界过敏性气道疾病（哮喘、鼻炎、鼻窦炎等）的患病率不断上升，尽管有这些统计数据，但关于驱动异常 Th2 免疫的过程仍然有很多未知之处。进一步了解驱动这些异常 Th2 免疫反应的机制将为我们提供开发新治疗方法的新途径。最近的证据表明，细胞因子 IL-33、及其受体 ST2 对调节异常 Th2 反应具有深远影响，并且在过敏性疾病中显着失调，但人们知之甚少先天免疫介质已被证明在调节 Th2 反应中发挥着核心作用，我们之前的工作已经使用 Th2 过敏性气道炎症小鼠模型证明了补体途径在调节肺部异常 2 型反应中的核心作用。我们提供的证据表明，过敏毒素（C3a 和 C5a）可调节对过敏原的过敏反应，并可直接调节 IL-33 的产生 IL-33-ST2 途径已被证明可驱动 2 型过敏性疾病。我们的初步数据表明，补体通过多种非互斥途径调节异常 2 型反应：直接调节 IL-33 的产生。提出了三个具体目标，以加深我们对肺上皮细胞调节的理解。过敏毒素的 IL-33-ILC2 轴将进一步了解过敏原诱导的 IL-33 的过敏毒素调节作用。具体目标 2 将确定过敏毒素信号在 ILC 调节 IL-13 产生中的作用。目标 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目前对先天 2 型反应如何发展的理解。我们的研究将开始表征过敏毒素信号传导的核心作用。补体途径平衡肺部先天 2 型反应的结果更好地了解这些新途径将使我们能够确定针对当前未得到充分服务的肺部 2 型反应失调个体的治疗干预的新目标。疗法。