MECHANISMS OF CHEMOKINE-INDUCED INFLAMMATION IN HUMANS

趋化因子家族C-C分支的几个成员在过敏性炎症期间与组织嗜酸性粒细胞的产生密切相关，这是由于它们对嗜酸性粒细胞具有有效和选择性的趋化活性。由于嗜酸性粒细胞被认为是过敏性疾病中观察到的组织损伤的原因，因此提高对其在体内募集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攻击模型，我们用它来表征人体组织对RANTES的反应。我们注意到，与过敏受试者相比，非过敏受试者的嗜酸性粒细胞募集明显延迟。Aim 1中描述的研究旨在测试嗜酸性粒细胞启动状态或CCR3表达或功能是否解释了这一结果。我们最近发现上皮细胞（Aim 2）和内皮细胞（Aim 3）表达一种功能性的CCR3，迄今为止只在白细胞、肥大细胞和小胶质细胞中被描述，接下来的Aims研究将继续进行。我们将重点研究与过敏性疾病相关的细胞因子家族，即Th1和Th2细胞因子对CCR3表达的调控。功能研究将集中在细胞迁移、诱导粘附分子表达、细胞因子产生和增殖。为了进一步了解这种受体的生物学特性，我们将确定上皮或内皮细胞CCR3的表达是否随疾病状态（过敏与非过敏）而变化，以及过敏原挑战是否会调节过敏受试者的基线表达。这项拨款提案将测试体内趋化因子反应取决于几个因素的总体假设。包括白细胞的启动和相关趋化因子受体在白细胞和实质细胞（如上皮细胞和内皮细胞）上的表达和功能。这些研究的结果可能为趋化因子诱导皮肤细胞募集的机制提供见解，并可能确定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.