Innate and Adaptive Immune Cell Cross-Talk in Lung Allergy

肺部过敏中的先天性和适应性免疫细胞交叉对话

• 批准号: 7476187
• 负责人: Richard M Locksley
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476187
• 关键词: Accounting; Adjuvant; Affect; Allergens; Allergic; Animal Model; Antibodies; Antigens; Aspergillus; Asthma; Attenuated; B-Lymphocytes; Bacterial Infections; Basophils; Biological Markers; CD4 Positive T Lymphocytes; Cell Wall; Cells; Characteristics; Chitin; Chitinase; Clinical; Complex; Crustacea; Dendritic Cells; Dendritic cell activation; Developed Countries; Developing Countries; Disease; Elements; Elevation; Feedback; Fibrosis; Gene-Modified; Helminths; Helper-Inducer T-Lymphocyte; Human; Hyperplasia; Hypersensitivity; IgE; Immune; Immune response; Immunity; Incidence; Infiltration; Inflammation; Inflammatory; Insecta; Interleukin-13; Interleukin-4; Knowledge; Lead; Ligands; Lung; Lung diseases; Mediating; Modeling; Mucous Membrane; Mucous body substance; Mus; Numbers; Patients; Phenotype; Prevalence; Process; Proteins; Regulation; Reporting; Role; Signal Transduction; Structure of lymph node of thorax; Structure of parenchyma of lung; System; T-Lymphocyte; Th1 Cells; Th2 Cells; Thinking; Tissues; United States; Viral; airborne allergen; airway hyperresponsiveness; antigen challenge; arginase; cell type; cytokine; environmental agent; eosinophil; fungus; human disease; human study; immunopathology; in vivo; insight; lung injury; lymph nodes; macrophage; mast cell; microbial; mouse model; neutrophil; novel; receptor; research study; response

Asthma is a complex inflammatory disease thought to reflect a dysregulated immune state that is established by elevated levels of the cytokines IL-4 and IL-13 in lung tissues. Increased numbers of innate and adaptive IL-4/IL-13-expressing cells, including Th2 cells, eosinophils, basophils and mast cells are found in chronically affected lung, and elevated levels of IgE are believed to contribute to sensitivity to aeroallergens. Despite the discovery of microbial ligands for receptors that induce inflammatory T helper cells subsets, including Th1 cells and Th17 cells, few molecular markers are known which induce immune responses by the characteristic cell types involved in allergy and asthma. We have recently discovered that a common constituent associated with many allergens is capable of inducing influx of eosinophils and basophils into the lungs of mice. Further, instillation induced the accumulation of alternatively activated macrophages, which are increasingly being recognized as a critical element of allergic immunity. This project will explore the contributions by this constituent component of helminths, insects and fungal cell walls in provoking changes in dendritic cells that mediate differentiation of Th2 cells, recruitment of innate IL-4/IL-13-producing cells, induction of B cell responses leading to IgE and lgG1, and ultimately a mucosal and tissue response. Using mice with genes modified to report faithful expression of key components of Th2-associated immunity, three specific aims are proposed: 1. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing dendritic cell activation in vivo. 2. To assess the role of chitin as an adjuvant and as a component of a fungal extract of Aspergillus in inducing Th2 cells and IL-4-dependent antibody isotypes. 3. To assess the role of chitin in the induction of feedback mechanisms that limit the inflammatory process in the lungs. LAY SUMMARY: The prevalence of asthma remains extensive in the United States and other developed countries. Knowledge of precise environmental agents that contribute to asthma and that can be studied in model animal systems is incomplete. This proposal will use mice to study novel and relevant mechanisms.

哮喘是一种复杂的炎症性疾病，被认为反映了已建立的免疫状态失调 肺组织中细胞因子 IL-4 和 IL-13 水平升高。先天性和适应性的数量增加 IL-4/IL-13 表达细胞，包括 Th2 细胞、嗜酸性粒细胞、嗜碱性粒细胞和肥大细胞，存在于慢性 受影响的肺部，IgE 水平升高被认为会导致对空气过敏原的敏感性。尽管 发现了诱导炎症 T 辅助细胞亚群受体的微生物配体，包括 Th1 细胞和 Th17 细胞，很少有分子标记能够诱导免疫反应 与过敏和哮喘有关的特征细胞类型。我们最近发现一个常见的 与许多过敏原相关的成分能够诱导嗜酸性粒细胞和嗜碱性粒细胞流入 老鼠的肺。此外，滴注诱导了替代激活的巨噬细胞的积累，这 越来越多地被认为是过敏性免疫的关键因素。该项目将探索 蠕虫、昆虫和真菌细胞壁的这种组成成分在引发变化方面的贡献 在介导 Th2 细胞分化的树突状细胞中，招募先天产生 IL-4/IL-13 的细胞， 诱导 B 细胞反应产生 IgE 和 IgG1，并最终引起粘膜和组织反应。使用 基因经过修饰的小鼠能够忠实地表达 Th2 相关免疫的关键成分，三 提出了具体目标： 1. 评估甲壳素作为佐剂和曲霉真菌提取物成分的作用 诱导体内树突状细胞活化。 2. 评估甲壳素作为佐剂和曲霉真菌提取物成分的作用 诱导 Th2 细胞和 IL-4 依赖性抗体同种型。 3. 评估几丁质在诱导限制炎症过程的反馈机制中的作用 肺部。 简单总结：哮喘在美国和其他发达国家的患病率仍然很高 国家。关于导致哮喘的精确环境因素的知识，可以在以下领域进行研究： 模型动物系统不完整。该提案将使用小鼠来研究新颖的相关机制。