Cockroach Allergen-Induced Airway Inflammation

蟑螂过敏原引起的气道炎症

基本信息

批准号：
7350228
负责人：
Nicholas W Lukacs
金额：
$ 38.28万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7350228
关键词：
5-(6)-carboxyfluorescein diacetate succinimidyl ester Address Adolescent Adoptive Transfer Allergens Allergic Antigens Asthma Attenuated Bronchial Injury CCL20 gene CCR6 gene CCR8 gene Cells Child Chronic Classification Complex Crowding Data Defect Dendritic Cells Development Dictyoptera Disease Effector Cell Functional disorder Gene Deletion Goals Green Fluorescent Proteins Human Hypersensitivity Immune Immune Cell Activation Immune response Inflammatory Response Intervention Investigation Label Lead Leukocytes Ligands Lung Lymphocyte Lymphocyte Activation Maintenance Modeling Morbidity - disease rate Mus Numbers Obstruction Pattern Pharmacy (field)Phenotype Physiology Play Population Positioning Attribute Process Production Proteins Relative (related person)Reporting Research Research Personnel Role Series Severities T-Lymphocyte Technology Th2 Cells Thinking airway hyperresponsiveness airway inflammation allergic airway disease allergic airway inflammation asthmatic airway attenuation base chemokine chemokine receptor cockroach allergen cytokine design drug development eosinophil in vivo inner city knockout animal lymph nodes migration mouse model neutralizing antibody programs receptor research study response success trafficking urban area

项目摘要

Peribronchial leukocyte accumulation and activation is a major disease factor during development of asthmatic airway responses that leads to chronic airway disease. In particular, lymphocytes and eosinophils have been reported to be primary populations associated with induction of bronchial injury, and are thought to participate in bronchial obstruction and airway hyperreactivity. Our investigations of the allergic airway response have identified chemokine receptors that are upregulated during the allergen-induced response within the airway. In particular, the expression of CCR6 appears to correlate with disease development within our model of cockroach allergen-induced disease and deletion of this protein significantly attenuates the pathophysiology. Our data suggest that this chemokine receptor plays critical roles in the allergic response, both for localization of T lymphocytes and for activation of the cells within the draining lymph nodes of the lung. Our hypothesis is that CCR6 and its ligand, CCL20, have multiple roles in the development of the pathophysiologic airway responses during allergen-specific activation involving both T lymphocytes and dendritic cells (DC). We will utilize a series of specific experiments designed to identify the mechanism(s) of recruitment and activation of T lymphocytes and dendritic cells during the development of the allergen-induced disease. Our studies will address important questions to identify the basic mechanisms involved in these processes including, 1) What lymphocyte populations express CCR6 and are they important for the development of the allergic responses within the airways and/or activation within the lymph nodes? 2) Does the expression of the CCR6 ligand CCL20 correspond to the localization of lymphocytes and dendritic cells during the allergic response? 3) Is the defect of CCR6 deletion centered on lymph node and/or lung localization of T lymphocytes? 4) Does CCR6 expression on dendritic cells have a contributing role of the developing allergic airway disease? 5) Does activation of DCs or lymphocytes via CCR6 impact directly on the immune phenotype of the response? 6) What is the expression pattern and in vivo function of CCL20 for development of the allergen-induced airway responses? Together, addressing these questions will allow us to outline the mechanisms involved in this complex inflammatory response using adoptive transfer and gene deletion technology. In addition, we will utilize cells from GFP expressing mice and CFSE labeled cells to allow analysis of trafficking of cells that have been transferred in vivo. The proposal identifies that the complexity of these responses appears to involve both T cells and DC that express CCR6 and are required for the full activation of the allergen-driven responses.

支气管周围白细胞积聚和激活是导致慢性气道疾病的哮喘气道反应发展过程中的主要疾病因素。特别是，据报道淋巴细胞和嗜酸性粒细胞是与诱导支气管损伤相关的主要群体，并且被认为参与支气管阻塞和气道高反应性。我们对过敏性气道反应的研究发现，在过敏原诱导的气道反应期间，趋化因子受体上调。特别是，CCR6 的表达似乎与我们的蟑螂过敏原诱导疾病模型中的疾病发展相关，并且删除该蛋白可显着减弱病理生理学。我们的数据表明，这种趋化因子受体在过敏反应中发挥着关键作用，无论是对于 T 淋巴细胞的定位还是对于肺引流淋巴结内细胞的激活。我们的假设是，CCR6 及其配体 CCL20 在涉及 T 淋巴细胞和树突状细胞 (DC) 的过敏原特异性激活期间的病理生理气道反应的发展中具有多种作用。我们将利用一系列具体实验来确定过敏原诱发疾病发展过程中 T 淋巴细胞和树突状细胞的招募和激活机制。我们的研究将解决重要问题，以确定这些过程中涉及的基本机制，包括：1）哪些淋巴细胞群表达 CCR6，它们对于气道内过敏反应的发展和/或淋巴结内的激活是否重要？ 2）CCR6配体CCL20的表达是否与过敏反应过程中淋巴细胞和树突状细胞的定位相对应？ 3) CCR6缺失的缺陷是否集中在T淋巴细胞的淋巴结和/或肺定位上？ 4) 树突状细胞上的 CCR6 表达是否对过敏性气道疾病的发生有影响？ 5) 通过 CCR6 激活 DC 或淋巴细胞是否直接影响反应的免疫表型？ 6) CCL20 在过敏原诱导的气道反应中的表达模式和体内功能是什么？总之，解决这些问题将使我们能够利用过继转移和基因删除技术概述这种复杂炎症反应所涉及的机制。此外，我们将利用表达 GFP 的细胞小鼠和 CFSE 标记的细胞可以分析体内转移的细胞的运输。该提案指出，这些反应的复杂性似乎涉及表达 CCR6 的 T 细胞和 DC，并且是过敏原驱动反应完全激活所必需的。