Airway Inflammation-Related Inhibition of Disease (AIRID)

气道炎症相关疾病的抑制 (AIRID)

• 批准号: 7545867
• 负责人: LAUREN E COHN
• 金额: $ 41.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545867
• 关键词: Animals; Antigens; Asthma; Attenuated; Breathing; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic lung disease; Data; Development; Disease; Employee Strikes; Environment; Enzymes; Eosinophilia; Epithelial; Epithelial Cells; Exposure to; Extrinsic allergic alveolitis; Extrinsic asthma; Goals; Histologic; IRAK3 gene; Immune; Immune response; Immunofluorescence Immunologic; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Knock-in Mouse; Knockout Mice; Ligands; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mucous body substance; Mus; Pathway interactions; Pattern; Population; Production; Pyroglyphidae; Regulatory Pathway; Respiratory System; Respiratory tract structure; Role; Saccharopolyspora; Sarcoidosis; Signal Transduction; Small Interfering RNA; Specificity; Symptoms; System; T-Lymphocyte; Th2 Cells; airway hyperresponsiveness; airway inflammation; arginase; inhibitor/antagonist; insight; knock-down; macrophage; novel; pathogen; protective effect; respiratory; response; tool

DESCRIPTION (provided by applicant): We defined a novel regulatory pathway in the respiratory tract. In a murine model, we showed that Th1- and Th2-induced airway inflammation followed by repeated exposure to inhaled antigen leads to a state of immunosuppression. Challenge of these animals with a marked population of TCR Tg effector Th1 or Th2 cells results in striking inhibition of inflammation and effector Th cells. In Th2 models, AHR, mucus and eosinophilia are reduced. We call this pathway Airway Inflammation-Related Inhibition of Disease (AIRID). AIRID is antigen non-specific, can be induced in lymphocyte deficient mice and is associated with a population of TGF-21- expressing macrophages. Our latest studies show that AIRID is macrophage-mediated and requires TLR signals for its induction. We hypothesize that AIRID is a regulatory pathway in the lung that is induced by repeated exposure to inhaled pathogen-associated molecular patterns (PAMPs), resulting in differentiation of a population of immunosuppressive macrophages. AIRID results in potent inhibition of effector Th1 and Th2 responses through the production of macrophage- and epithelial-derived mediators. AIRID is a powerful method to inhibit effector T cell responses. This pathway may exist to block immune responses when there is repeated inhalational exposure to non-pathogenic substances and to resolve ongoing inflammatory responses. Induction of this pathway may offer potent, localized treatment of chronic T cell-mediated respiratory illnesses, such as asthma and sarcoidosis, and provide insights into the development of such diseases. In this proposal we will: Aim I. Define how innate immune signals stimulate AIRID. Aim II. Define mechanisms of immunosuppression in AIRID. Aim III. Determine if AIRID can be induced to treat inflammatory lung diseases. Project Narrative: This proposal investigates a novel protective pathway in the respiratory tract that controls lung inflammation. We will define the cells and factors that are responsible for the protective effect and determine if this pathway can be activated to treat chronic lung diseases, such as asthma and sarcoidosis.

描述（由申请人提供）：我们定义了呼吸道中的新调节途径。在鼠模型中，我们表明Th1和Th2诱导的气道炎症，然后反复暴露于吸入抗原会导致免疫抑制状态。这些动物具有明显的TCR TG效应子Th1或Th2细胞的挑战会导致炎症和效应TH细胞的抑制作用。在TH2模型中，AHR，粘液和嗜酸性粒细胞减少。我们称此通道气道炎症与疾病的抑制作用（AIRID）。 AIRID是抗原非特异性的，可以在淋巴细胞缺乏小鼠中诱导，并且与TGF-21-表达巨噬细胞的种群有关。我们的最新研究表明，AirID是巨噬细胞介导的，需要TLR信号才能诱导。我们假设AIRID是肺中的一种调节途径，它是通过反复暴露于与病原体相关的分子模式（PAMP）诱导的，导致了免疫抑制巨噬细胞的分化。通过产生巨噬细胞和上皮衍生的介体，导致对效应Th1和Th2反应的有效抑制。 AIRID是抑制效应T细胞反应的强大方法。当反复吸入非致病物质并解决持续的炎症反应时，这种途径可能会阻止免疫反应。该途径的诱导可能会提供对慢性T细胞介导的呼吸道疾病（例如哮喘和结节病）的有效局部治疗，并为这种疾病的发展提供了见解。在此提案中，我们将：AIM I。定义先天免疫信号如何刺激航空公司。目标II。定义AIRID中免疫抑制的机制。目标三。确定是否可以诱导AIRID治疗炎症性肺部疾病。项目叙述：该提案调查了控制肺部炎症的呼吸道中的一种新型保护途径。我们将定义负责保护作用的细胞和因素，并确定是否可以激活该途径以治疗慢性肺部疾病，例如哮喘和结节病。