Type 2 Innate Lymphoid Cells and Asthma

描述（由申请人提供）：本资助项目的长期目标是了解哮喘的免疫学机制。哮喘患者的气道炎症通常以嗜酸性粒细胞和产生Th2细胞因子的淋巴细胞数量增加为特征。然而，气道中Th2型CD4+ T细胞的发育和Th2细胞因子的持续和/或复发性产生的机制尚不完全清楚。最近，我们和其他研究人员在小鼠肺中发现了对IL-33有反应的新型2型先天淋巴样细胞（ILC2s）。气道暴露于空气过敏原可诱导肺部产生IL-33，外源性IL-33可促进抗原特异性th2型CD4+ T细胞的发育。此外，ILC2s和常规CD4+ T细胞协同作用，导致体外大量Th2细胞因子的产生。因此，我们假设ILC2s参与了暴露于空气中过敏原的呼吸道中强大的th2型免疫反应和持续炎症的发展，从而导致慢性气道疾病，如哮喘。在Aim 1中，我们将确定ILC2s在抗原特异性th2型CD4+ T细胞发育中的作用。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ILC2s如何参与肺中抗原特异性th2型CD4+ T细胞的发育和/或维持。在Aim 2中，我们将确定ILC2s和传统th2型CD4+ T细胞在哮喘中的作用。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），我们将剖析ILC2s和CD4+ T细胞之间的协同相互作用在持续气道炎症和肺部病理中的作用。在Aim 3中，我们将研究ILC2s在人类哮喘中的作用。我们将收集过敏性哮喘患者和对照个体的外周血标本，检查il -33反应性ILC2s是否在哮喘患者中增加和/或功能激活。我们已经开发了几个健壮的小鼠模型来解剖th2型免疫反应和气道炎症对空气中的过敏原。完成该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，目前在我们的实验室可用。一组杰出的研究人员，包括一名哮喘专家，将参与这个项目。因此，拟议的研究可能为暴露于环境过敏原后th2型免疫反应和气道炎症发展和持续的机制提供基本信息。它们将提供对哮喘发病机制的新认识，并将导致哮喘和其他th2型气道炎症疾病的新治疗和预防策略的发展。

DESCRIPTION (provided by applicant): 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.