Type 2 Innate Lymphoid Cells and Asthma

项目摘要/摘要 该项目的长期目标是了解哮喘的免疫学机制。呼吸道炎症 哮喘患者的特点通常是淋巴细胞增多，产生2型细胞因子。 然而，与2型细胞因子持续和/或反复产生有关的机制 人们并不完全理解航空公司。 在过去的几年里，关于2型免疫机制的研究取得了显著的进展。 第二组先天淋巴样细胞(ILC2s)能迅速产生大量的2型细胞因子 发现并牵涉到2型免疫的先天手臂。最近的研究结果表明， ILC2s调节免疫的适应性臂及其高度的可塑性。因此，首要目标是 这一续订申请的目的是将ILC2基础科学中的这些新发现转化为 哮喘的免疫学机制。我们将检验这一假设，即ILC2在持久和 哮喘患者反复出现的呼吸道炎症。 在目标1中，我们将确定肺ILC2在小鼠慢性呼吸道炎症模型中的作用。通过 利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 ILC2s和Th2型CD4+T细胞在慢性呼吸道炎症中的作用在目标2中，我们将阐明基因和 小鼠肺ILC2s的功能可塑性。寄居在常规特定病原体中的小鼠的免疫系统- 自由环境类似于人类新生儿。通过使用最近开发的一种新的小鼠模型 复制了人类成人型免疫系统，我们将研究肺ILC2的功能可塑性 这种环境以及它们促进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在人类慢性呼吸道疾病中的作用。慢性鼻-鼻窦炎(CRS) 常与哮喘有关。通过使用建立的临床方案来评估CRS患者在 疾病的自然恶化，我们将研究ILC2的功能是如何在 疾病的过程。 这项应用结合了小鼠的机械学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。完成这一项目所需的工具和技术专长已经到位。因此， 拟议的研究可能会提供有关2型呼吸道炎症的基本信息。 哮喘和ILC2s受累患者的复发和持久性。澄清免疫学 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呼吸道疾病。

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.