Cockroach Allergen-Induced Airway Inflammation

支气管周围白细胞的聚集和激活是哮喘气道反应发展过程中的一个主要疾病因素，导致慢性呼吸道疾病。特别是，淋巴细胞和嗜酸性粒细胞被报道为与诱导支气管损伤有关的主要群体，并被认为参与了支气管阻塞和呼吸道高反应性。我们对过敏性呼吸道反应的研究发现，趋化因子受体在过敏原诱导的呼吸道反应中上调。特别是，在我们的蟑螂变应原诱导的疾病模型中，CCR6的表达似乎与疾病的发展相关，该蛋白的缺失显著减弱了 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起着关键作用，无论是对T淋巴细胞的定位，还是对肺引流淋巴结内细胞的激活。我们的假设是，CCR6及其配体CCL20在包括T淋巴细胞和树突状细胞(DC)在内的过敏原特异性激活过程中，在呼吸道病理生理反应的发展中具有多种作用。我们将利用一系列特定的实验来确定在过敏原诱导的疾病发展过程中T淋巴细胞和树突状细胞招募和激活的机制(S)。我们的研究将解决重要的问题，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？它们对呼吸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中淋巴细胞和树突状细胞的定位相对应？3)CCR6缺失缺陷是否集中在淋巴结和/或T淋巴细胞的肺定位？4)树突状细胞上CCR6的表达是否在过敏性呼吸道疾病的发展中起作用？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)表达是什么CCL20在过敏原诱导的呼吸道反应中的模式和体内功能？总之，解决这些问题将使我们能够概述使用过继转移和基因缺失技术进行这种复杂的炎症反应所涉及的机制。此外，我们还将利用GFP中的细胞表达 小鼠和CFSE标记的细胞，以便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，它们是完全激活过敏原驱动的反应所必需的。

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.