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，被认为反映了一种免疫失调状态， 肺组织中细胞因子IL-4和IL-13水平升高。先天和适应性的数量增加 IL-4/IL-13表达细胞，包括Th 2细胞、嗜酸性粒细胞、嗜碱性粒细胞和肥大细胞，在慢性炎症中发现。 受影响的肺和IgE水平升高被认为有助于对空气过敏原的敏感性。尽管 发现了诱导炎性T辅助细胞亚群的受体的微生物配体，包括 Th 1细胞和Th 17细胞，很少有已知的分子标志物通过免疫球蛋白诱导免疫应答。 与过敏和哮喘有关的典型细胞类型。我们最近发现， 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，滴注诱导了交替激活的巨噬细胞的积累， 越来越多地被认为是过敏性免疫的关键因素。本项目将探讨 蠕虫、昆虫和真菌细胞壁的这种组成成分在引起变化方面的贡献 在介导Th 2细胞分化的树突细胞中，募集先天性IL-4/IL-13产生细胞， 诱导B细胞应答，导致IgE和IgG 1，并最终导致粘膜和组织应答。使用 基因修饰的小鼠报告了Th 2相关免疫的关键成分的忠实表达， 提出了具体目标： 1.为了评估几丁质作为佐剂和作为曲霉菌提取物的组分的作用， 在体内诱导树突细胞活化。 2.为了评估几丁质作为佐剂和作为曲霉菌提取物的组分的作用， 诱导Th 2细胞和IL-4依赖性抗体同种型。 3.为了评估几丁质在诱导限制炎症过程的反馈机制中的作用， 肺 摘要：哮喘的患病率在美国和其他发达国家仍然很高。 国家了解导致哮喘的确切环境因素，并可在 动物模型是不完整的。该提案将使用小鼠研究新的相关机制。