Cockroach Allergen-Induced Airway Inflammation

支气管周围白细胞聚集和活化是哮喘气道反应发展过程中的一个主要疾病因素，可导致慢性气道疾病。特别是，淋巴细胞和嗜酸性粒细胞已被报道为与诱导支气管损伤相关的主要群体，并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已经确定了在气道内过敏原诱导的反应过程中上调的趋化因子受体。特别是，CCR 6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至关重要的作用，无论是定位的T淋巴细胞和肺引流淋巴结内的细胞的激活。我们的假设是，CCR 6和它的配体，CCL 20，在过敏原特异性激活过程中，涉及T淋巴细胞和树突状细胞（DC）的病理生理气道反应的发展中具有多重作用。我们将利用一系列特定的实验，旨在确定过敏原诱导的疾病发展过程中T淋巴细胞和树突状细胞的募集和激活机制。我们的研究将解决重要的问题，以确定在这些过程中涉及的基本机制，包括，1）什么淋巴细胞群体表达CCR 6，他们是重要的气道内的过敏反应的发展和/或淋巴结内的激活？2)CCR 6配体CCL 20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)CCR 6缺失的缺陷是否集中于T淋巴细胞的淋巴结和/或肺定位？4)树突状细胞上CCR 6的表达是否与变应性气道疾病的发生有关？5)通过CCR 6激活DC或淋巴细胞是否直接影响应答的免疫表型？6)CCL 20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使用过继转移和基因缺失技术概述参与这种复杂炎症反应的机制。此外，我们将利用来自GFP表达的细胞， 小鼠和CFSE标记的细胞，以允许分析已经在体内转移的细胞的运输。该提案确定，这些反应的复杂性似乎涉及表达CCR 6的T细胞和DC，并且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.