MECHANISMS OF CHEMOKINE-INDUCED INFLAMMATION IN HUMANS

趋化因子家族的C-C分支的几个成员由于其对嗜酸性粒细胞的强效和选择性化学引诱活性而与变应性炎症期间组织嗜酸性粒细胞增多症的产生密切相关。由于嗜酸性粒细胞被认为是负责在过敏性疾病中观察到的组织损伤，提高他们的招聘在体内负责的因素的理解是必要的。我们已经开发了一种体内趋化因子的挑战模型，我们的特点是组织响应RANTES在人类。我们注意到，与过敏性受试者相比，非过敏性受试者的嗜酸性粒细胞募集明显延迟。目的1中描述的研究旨在测试嗜酸性粒细胞引发或CCR 3表达或功能的状态是否解释了该结果。以下目标中的研究将跟进我们最近令人兴奋的发现，即上皮细胞（Aim 2）和内皮细胞（Aim 3）表达功能性CCR 3，迄今为止仅在白细胞，肥大细胞和小胶质细胞上描述。我们将研究CCR 3表达的调节，重点是与过敏性疾病相关的细胞因子家族，即Th 1和Th 2细胞因子。功能研究将集中在细胞迁移，诱导粘附分子表达，细胞因子的产生和增殖。为了进一步了解这种受体的生物学，我们将确定上皮或内皮CCR 3表达是否因疾病状态（过敏性与非过敏性）而异，以及过敏原激发是否调节过敏性受试者的基线表达。这项拨款提案将测试体内趋化因子反应性取决于几个因素的总体假设。包括白细胞引发和白细胞和实质细胞（例如上皮细胞和内皮细胞）上相关趋化因子受体的表达和功能。这些研究的结果可能提供深入了解趋化因子诱导皮肤细胞募集的机制，并可能识别C-C趋化因子的全新生物学效应。

Several members of the C-C branch of the chemokine family have been strongly implicated in the generation of tissue eosinophilia during allergic inflammation, due to their potent and selective chemoattractant activity on eosinophils. Since eosinophils are believed to be responsible for the tissue damage observed in allergic diseases, an improved understanding of the factors responsible for their recruitment in vivo is imperative. We have developed an in vivo chemokine challenge model with which we characterized the tissue response to RANTES in humans. We noted a profound delay in eosinophil recruitment in nonallergic subjects as compared to allergic subjects. Studies described in Aim 1 are designed to test whether the state of eosinophil priming or CCR3 expression or function explain this result. Studies in following Aims will follow up on our recent exciting discovery that epithelial (Aim 2) and endothelial (Aim 3) cells express a functional CCR3, which to date has only been described on leukocytes, mast cells and microglial cells. We will study the regulation of CCR3 expression focusing on cytokine families that are relevant for allergic diseases, namely Th1 and Th2 cytokines. Functional studies will focus on cell migration, induction of adhesion molecule expression, cytokine production and proliferation. To provide further insight into the biology of this receptor, we will determine whether epithelial or endothelial CCR3 expression varies depending on disease status (allergic vs nonallergic ) and whether allergen challenge modulates the baseline expression in allergic subjects. This grant proposal will test the overall hypothesis that chemokine responsiveness in vivo is dependent on several factors. including leukocyte priming and expression and function of relevant chemokine receptors on leukocytes and parenchymal cells (such as epithelial and endothelial cells). Results of these studies are likely to provide insights into the mechanisms by which chemokines induce cutaneous cell recruitment and will likely identify entirely new biological effects of C-C chemokines.