Type 2 Innate Lymphoid Cells and Asthma

项目总结/摘要 这项资助计划的长期目标是了解哮喘的免疫机制。 哮喘患者的气道炎症通常以嗜酸性粒细胞数量增加为特征 和产生Th 2细胞因子的淋巴细胞。然而，Th 2型的发展所涉及的机制 气道中的CD 4 + T细胞和Th 2细胞因子的持续性和/或复发性产生并不完全是一种免疫调节因子。 明白 最近，我们和其他研究人员在小鼠肺中发现了新的2型先天淋巴细胞， （ILC 2），其响应于IL-33。呼吸道暴露于空气过敏原诱导肺中IL-33的产生， 外源IL-33的施用促进抗原特异性Th 2型CD 4 + T细胞的发育。 此外，ILC 2和常规的CD 4 + T细胞协同作用，导致ILC 2的产生。 体外大量Th 2细胞因子。因此，我们假设ILC 2参与了 呼吸道暴露中产生强烈的Th 2型免疫应答和持续性炎症 空气中的过敏原，导致慢性气道疾病，如哮喘。 在目的1中，我们将确定ILC 2s在抗原特异性Th 2型CD 4 + T细胞发育中的作用。 细胞通过体外实验和IL-33驱动的小鼠气道致敏模型，我们将研究 ILC 2如何参与抗原特异性Th 2型CD 4 + T细胞的发育和/或维持， 肺目的2：探讨ILC 2s和传统Th 2型CD 4 + T细胞在哮喘发病中的作用。 通过使用慢性哮喘小鼠模型（即反复暴露于环境过敏原的小鼠），我们将 分析ILC 2和CD 4 + T细胞在持续气道中协同作用的作用， 炎症和肺部病理学。在目标3中，我们将研究ILC 2在人类哮喘中的作用。我们将 从过敏性哮喘患者和对照个体收集外周血样本， 哮喘患者中IL-33应答性ILC 2是否增加和/或功能性激活。 我们已经开发了几种强大的小鼠模型来剖析Th 2型免疫应答， 空气过敏原引起的气道炎症。完成此项目所需的所有工具，包括 基因缺陷小鼠、细胞因子报告小鼠和过继细胞转移模型，目前可在我们的实验室获得。 实验室一个杰出的研究小组，包括一名哮喘专家，将参与这项研究。 项目因此，拟议的研究可能会提供有关 Th 2型免疫应答和气道炎症的发生和持续机制 暴露于环境过敏原。它们将为哮喘的发病机制提供新的认识 并将导致开发新的治疗和预防策略，用于哮喘和其他Th 2型 气道炎症性疾病。

PROJECT SUMMARY/ABSTRACT The long-term goal of this grant project is to understand the immunological mechanisms of asthma. Airway inflammation in patients with asthma is generally characterized by increased numbers of eosinophils and lymphocytes producing Th2 cytokines. However, the mechanisms involved in development of Th2-type CD4+ T cells and persistent and/or recurrent production of Th2 cytokines in the airways are not fully understood. Recently, we and other investigators have identified in mouse lungs novel type 2 innate lymphoid cells (ILC2s) that are responsive to IL-33. Airway exposure to aeroallergens induces IL-33 production in the lungs, and administration of exogenous IL-33 promotes development of antigen-specific Th2-type CD4+ T cells. Furthermore, ILC2s and conventional CD4+ T cells work together synergistically, resulting in production of large quantities of Th2 cytokines in vitro. Therefore, we hypothesize that ILC2s are involved in the development of robust Th2-type immune responses and persistent inflammation in respiratory tract exposed to airborne allergens, leading to chronic airway diseases such as asthma. In Aim 1, we will determine the roles of ILC2s in development of antigen-specific Th2-type CD4+ T cells. By using in vitro experiments and IL-33-driven mouse airway sensitization models, we will investigate how ILC2s are involved in the development and/or maintenance of antigen-specific Th2-type CD4+ T cells in the lungs. In Aim 2, we will determine the roles of ILC2s and conventional Th2-type CD4+ T cells in asthma. By using a mouse model of chronic asthma (i.e. mice exposed repeatedly to environmental allergens), we will dissect the roles for synergistic interactions between ILC2s and CD4+ T cells in persistent airway inflammation and lung pathology. In Aim 3, we will investigate the roles of ILC2s in human asthma. We will collect peripheral blood specimens from allergic asthma patients and from control individuals and examine whether IL-33-responsive ILC2s are increased and/or functionally activated in patients with asthma. We have developed several robust mouse models to dissect the Th2-type immune responses and airway inflammation to airborne allergens. All of the tools necessary to accomplish this project, including gene-deficient mice, cytokine reporter mice and adoptive cell transfer models, are currently available in our laboratory. An outstanding group of investigators, including an asthma specialist, will participate in this project. Therefore, the proposed studies are likely to provide fundamental information regarding the mechanisms by which Th2-type immune responses and airway inflammation develop and persist after exposure to environmental allergens. They will provide a new understanding of the pathogenesis of asthma and will lead to the development of novel treatments and prevention strategies for asthma and other Th2-type airway inflammatory disorders.