MECHANISMS OF CHEMOKINE-INDUCED INFLAMMATION IN HUMANS

趋化因子引起的人类炎症机制

基本信息

批准号：
6838782
负责人：
Lisa Ann Beck
金额：
$ 32.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2007-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6838782
关键词：
atopy chemokine clinical research cytokine receptors eosinophil epithelium human subject human tissue inflammation leukocyte activation /transformation receptor expression respiratory epithelium skin

项目摘要

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.

趋化因子家族的C-C分支的几个成员由于对嗜酸性粒细胞的有效和选择性的趋化剂活性，在过敏性炎症过程中与组织嗜酸性粒细胞的产生非常重要。由于嗜酸性粒细胞被认为是导致在过敏性疾病中观察到的组织损伤的原因，因此必须提高对导致其体内招募的因素的理解。我们开发了一个体内趋化因子挑战模型，我们通过该模型表征了人类对兰特的组织反应。我们注意到与过敏受试者相比，非过敏性受试者的嗜酸性粒细胞募集延迟。 AIM 1中描述的研究旨在测试嗜酸性粒细胞启动或CCR3表达或功能是否解释了这一结果。以下目标的研究将跟进我们最近的令人兴奋的发现，即上皮（AIM 2）和内皮（AIM 3）细胞表达功能性CCR3，迄今为止，该功能仅在白细胞，肥大细胞和小胶质细胞上进行了描述。我们将研究针对与过敏性疾病有关的细胞因子家族的CCR3表达的调节，即Th1和Th2细胞因子。功能研究将集中于细胞迁移，诱导粘附分子表达，细胞因子产生和增殖。为了进一步了解该受体的生物学，我们将确定上皮或内皮CCR3表达是否取决于疾病状态（过敏性与非过敏性）以及过敏素挑战是否在过敏受试者中调节基线表达。该赠款提案将检验总体假设，即体内趋化因子反应性取决于几个因素。包括白细胞启动以及相关趋化因子受体在白细胞和实质细胞（例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会提供有关趋化因子诱导皮肤细胞募集的机制的见解，并可能鉴定出C-C趋化因子的全新生物学作用。