Type 2 Innate Lymphoid Cells and Asthma

项目摘要/摘要 这一赠款项目的长期目标是了解哮喘的免疫学机制。 哮喘患者的呼吸道炎症通常以嗜酸性粒细胞增多为特征。 以及产生Th2细胞因子的淋巴细胞。然而，Th2型细胞的发生机制 呼吸道中的CD4+T细胞和Th2细胞因子的持续性和/或复发性产生还不完全 明白了。 最近，我们和其他研究人员在小鼠肺中发现了新的2型固有淋巴样细胞。 (ILC2)对IL-33有反应。呼吸道暴露于空气变应原可诱导肺部产生IL-33， 注射外源性IL-33可促进抗原特异性Th2型CD4+T细胞的发育。 此外，ILC2和传统的CD4+T细胞协同工作，导致产生 体外大量表达Th2细胞因子。因此，我们假设ILC2参与了 暴露于呼吸道的Th2型免疫反应和持续性炎症的形成 空气传播的过敏原，导致哮喘等慢性呼吸道疾病。 在目标1中，我们将确定ILC2在抗原特异性Th2型CD4+T细胞发育中的作用 细胞。通过体外实验和IL-33驱动的小鼠呼吸道致敏模型，我们将研究 ILC2如何参与抗原特异性Th2型CD4+T细胞的发育和/或维持 肺部。在目标2中，我们将确定ILC2和传统的Th2型CD4+T细胞在哮喘中的作用。 通过使用慢性哮喘的小鼠模型(即反复暴露于环境过敏原的小鼠)，我们将 剖析ILC2与CD4+T细胞在持续气道协同作用中的作用 炎症和肺部病理。在目标3中，我们将研究ILC2在人类哮喘中的作用。我们会 采集过敏性哮喘患者和对照组的外周血样，并进行检测 哮喘患者的IL-33反应性ILC2是否增加和/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 呼吸道对空气传播的过敏原的炎症。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。包括一名哮喘专家在内的一批杰出的研究人员将参与此次活动。 项目。因此，拟议的研究可能会提供有关 Th2型免疫反应和呼吸道炎症发生和持续的机制 暴露于环境过敏原。这将为哮喘的发病机制提供新的认识。 并将导致开发针对哮喘和其他Th2型的新的治疗和预防策略 呼吸道炎症性疾病。

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.