Type 2 Innate Lymphoid Cells and Asthma

2 型先天淋巴细胞与哮喘

• 批准号: 10063304
• 负责人: Hirohito Kita
• 金额: $ 49.13万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-27 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063304
• 关键词: Address; Adult; Airway Disease; Animals; Asthma; Basic Science; Biological Factors; Blood; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical Protocols; Development; Disease; Environment; Environmental Risk Factor; Epithelial; Epithelium; Exposure to; Financial Hardship; Functional disorder; Genetic; Goals; Grant; House mice; Human; IL2RB gene; Immune; Immune response; Immune system; Immunity; Immunologics; Immunologist; Inflammation; Interleukin-13; Interleukins; Laboratory mice; Lung; Lymphocyte; Lymphoid Cell; Mediating; Medical; Microbe; Modeling; Mus; Nasal Polyps; Pathogenesis; Pathologic; Pathway interactions; Patients; Physiological; Play; Prevention; Prevention strategy; Process; Production; RORA gene; Recurrence; Research; Research Personnel; Respiratory Tract Diseases; Role; Single Nucleotide Polymorphism; Source; TSLP gene; Technical Expertise; Testing; Therapeutic; Translating; adaptive immunity; airborne allergen; airway hyperresponsiveness; airway inflammation; arm; cell type; chronic inflammatory disease; chronic rhinosinusitis; cytokine; environmental allergen; eosinophil; functional plasticity; genome wide association study; germ free condition; lipid mediator; mouse model; neonate; novel; novel strategies; respiratory; response; tool

PROJECT SUMMARY/ABSTRACT This project's long-term goal is to understand asthma's immunological mechanisms. Airway inflammation in patients with asthma is generally characterized by increased lymphocytes producing type 2 cytokines. However, the mechanisms involved in persistent and/or recurrent production of type 2 cytokines in the airways are not entirely understood. Notable progress regarding the mechanisms of type 2 immunity has been made in the past several years. Group 2 innate lymphoid cells (ILC2s) that rapidly produce large quantities of type 2 cytokines have been identified and are implicated in the innate arm of type 2 immunity. More recent findings suggest the ability of ILC2s to regulate the adaptive arm of immunity and their high degree of plasticity. Thus, the primary objective of this renewal application is to translate these new discoveries in the basic science of ILC2s to the immunologic mechanisms of asthma. We will test the hypothesis that ILC2s play a vital role in persistent and recurrent airway inflammation in asthma. In Aim 1, we will determine the roles of lung ILC2s in a chronic airway inflammation model in mice. By using a model in which mice are repeatedly exposed to natural airborne allergens, we will dissect the roles for ILC2s and Th2-type CD4+ T cells in chronic airway inflammation. In Aim 2, we will elucidate the genetic and functional plasticity of lung ILC2s in mice. The immune system of mice housed in a regular specific pathogen- free environment is similar to human neonates. Through the use of a recently developed novel mouse model that replicates a human adult-like immune system, we will investigate the functional plasticity of lung ILC2s in that environment and how their abilities to promote type 2 inflammation are modulated. In Aim 3, we will investigate the roles of ILC2s in a chronic airway disease in humans. In patients, chronic rhinosinusitis (CRS) is often associated with asthma. By using an established clinical protocol to evaluate CRS patients during a natural exacerbation of the disease, we will investigate how functions of ILC2s are regulated dynamically in the disease process. This application integrates mechanistic studies in mice and a proof-of-concept study in humans. It represents collaborative efforts among basic science and translational immunologists and clinician investigators. The tools and technical expertise necessary to accomplish this project are in place. Therefore, the proposed studies will likely provide fundamental information regarding type 2 airway inflammation recurrence and persistence in patients with asthma and ILC2s involvement. Clarification of the immunological mechanisms involved in the disease process will lead to development of novel strategies for the prevention and treatment of asthma and related chronic airway disorders.

项目概要/摘要 该项目的长期目标是了解哮喘的免疫机制。气道炎症 哮喘患者的一般特征是产生2型细胞因子的淋巴细胞增多。 然而，参与持续和/或反复产生 2 型细胞因子的机制 航空公司尚未完全了解。 过去几年，2 型免疫机制方面取得了显着进展。 快速产生大量 2 型细胞因子的 2 类先天淋巴细胞 (ILC2) 已被识别并与 2 型免疫的先天臂有关。最近的研究结果表明， ILC2 调节免疫适应性臂及其高度可塑性。因此，首要目标 此次更新应用的目的是将ILC2基础科学中的这些新发现转化为 哮喘的免疫机制。我们将检验这样的假设：ILC2 在持久性和持续性方面发挥着至关重要的作用。 哮喘复发性气道炎症。 在目标 1 中，我们将确定肺 ILC2 在小鼠慢性气道炎症模型中的作用。经过 使用小鼠反复暴露于天然空气传播过敏原的模型，我们将剖析其作用 ILC2 和 Th2 型 CD4+ T 细胞在慢性气道炎症中的作用。在目标 2 中，我们将阐明遗传和 小鼠肺 ILC2 的功能可塑性。小鼠的免疫系统被安置在一种常规的特定病原体中—— 自由环境类似于人类新生儿。通过使用最近开发的新型小鼠模型 复制类似成人的免疫系统，我们将研究肺 ILC2 的功能可塑性 该环境以及它们促进 2 型炎症的能力是如何被调节的。在目标 3 中，我们将 研究 ILC2 在人类慢性气道疾病中的作用。慢性鼻窦炎 (CRS) 患者 常与哮喘有关。通过使用既定的临床方案来评估 CRS 患者 随着疾病的自然恶化，我们将研究 ILC2 的功能如何在 疾病过程。 该应用程序整合了小鼠的机制研究和人类的概念验证研究。它 代表基础科学、转化免疫学家和临床医生之间的合作努力 调查人员。完成该项目所需的工具和技术专业知识已经到位。所以， 拟议的研究可能会提供有关 2 型气道炎症的基本信息 哮喘和 ILC2 受累患者的复发和持续性。免疫学的澄清 疾病过程中涉及的机制将导致制定新的预防策略 以及治疗哮喘和相关的慢性气道疾病。