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Type 2 Innate Lymphoid Cells and Asthma

2 型先天淋巴细胞与哮喘

基本信息

批准号：
10219332
负责人：
Hirohito Kita
金额：
$ 47.33万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-27 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219332
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 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

项目摘要

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.

项目总结/摘要该项目的长期目标是了解哮喘的免疫机制。气道炎症在哮喘患者中，通常以产生2型细胞因子的淋巴细胞增加为特征。然而，参与持续和/或复发的2型细胞因子产生的机制，气道并不完全清楚。在过去几年中，关于2型免疫机制的研究取得了显著进展。快速产生大量2型细胞因子的第2组先天性淋巴细胞（ILC 2）已被发现，被鉴定并与2型免疫的先天性臂有关。最近的研究结果表明， ILC 2调节免疫的适应性臂及其高度可塑性。因此，主要目标这项更新申请的目的是将ILC 2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ILC 2在持续性和非持续性免疫中发挥重要作用的假设。哮喘复发性气道炎症。在目的1中，我们将确定肺ILC 2在小鼠慢性气道炎症模型中的作用。通过使用小鼠反复暴露于天然空气过敏原的模型，我们将剖析 ILC 2s和Th 2型CD 4 + 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ILC 2的功能可塑性。把老鼠的免疫系统放在一个特定的病原体里- 自由环境与人类新生儿相似。通过使用最近开发的新型小鼠模型复制人类成人样免疫系统，我们将研究肺ILC 2的功能可塑性，以及它们促进2型炎症的能力是如何调节的。在目标3中，我们研究ILC 2在人类慢性气道疾病中的作用。慢性鼻窦炎（CRS）通常与哮喘有关。通过使用已建立的临床方案来评估CRS患者，疾病的自然恶化，我们将研究ILC 2的功能是如何动态调节的，疾病的过程。该应用整合了小鼠的机制研究和人类的概念验证研究。它代表了基础科学和转化免疫学家和临床医生之间的合作努力 investigators.完成这一项目所需的工具和技术专长已经到位。因此，我们认为，所提出的研究将可能提供有关2型气道炎症的基本信息哮喘和ILC 2参与的患者的复发和持续性。免疫学澄清参与疾病过程的机制将导致新的预防策略的发展，以及治疗哮喘和相关的慢性气道疾病。