INTEGRIN CD103-ROLE IN TH2 PULMONARY IMMUNE RESPONSES

整合素 CD103 在 TH2 肺免疫反应中的作用

• 批准号: 6388694
• 负责人: MANUELA CERNADAS
• 金额: $ 13.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388694
• 关键词: antigen antibody reaction; asthma; cell differentiation; cell migration; cytokine; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; gene expression; helper T lymphocyte; hybridomas; immunity; immunocytochemistry; immunoregulation; integrins; laboratory mouse; leukocyte activation /transformation; phenotype; protein structure function; respiratory hypersensitivity; single cell analysis; tissue /cell culture

Asthma, a disease which affects millions worldwide, represents a complex inflammatory disorder characterized by airway inflammation and airway hyperreactivity. Although multiple molecular signals and cells are involved in the pathogenesis of asthma, the CD4+ T lymphocyte has been clearly shown to play a critical role. Specifically, CD4+ T helper cells which are characterized by the secretion of Th2 cytokines. The immunologic pathways by which naive T helper cells differentiate into a Th2 phenotype, however, have yet to be clearly delineated. Integrin alphaE(CD103)beta7 is expressed on lymphocytes, dendritic cells and mast cells, cell types which have been implicated in asthma and the dynamic regulation of mucosal immune responses. The role of integrin alphaEbeta7 in the mediation of pulmonary allergic inflammation and airway reactivity was studied in an in vivo murine model of airway hyperresponsiveness, characterized by high levels of Th2 cytokines, airway hyperresponsiveness and pulmonary inflammation. Integrin alphaE deficient mice were found to have decreased pulmonary inflammation, airway reactivity and markedly reduced levels of Th2 cytokines. In vitro studies demonstrated unfractionated splenocytes from alphaE deficient mice produced significantly lower levels of Th2 cytokines than alphaE+/+ mice. Mixing studies, using purified populations of splenic CD4+ T cells and accessory cells from alphaE deficient and wild type mice, localized the regulation of CD4+ T cell differentiation to a Th2 phenotype to the accessory cell population. Given that alphaEbeta7 is expressed on 25 percent of splenic dendritic cells, the hypothesis that integrin alphaEbeta7 plays a critical role in the regulation of the phenotypic development of CD4+ T cells, mediated by alphaEbeta7 dendritic cells, was developed. To test this hypothesis, in vitro studies will be performed to demonstrate the role of alphaEbeta7+ dendritic cells in the differentiation of CD4+ T cells to a Th2 phenotype and to characterize their phenotypic and functional characteristics. Adoptive transfer experiments will be performed to determine the ability Of alphaEbeta7+ dendritic cells to mediate Th2 polarization in vivo and to confer airway hyperresponsiveness and pulmonary inflammation in response to aerosolized antigen challenge. The mechanisms by which expression of this integrin on dendritic cells mediates the differentiation of nave T helper cells and Th2 pulmonary immune responses will also be examined. These studies may provide significant insights into the role of integrin alphaEbeta7 in T helper cell differentiation and dendritic cell biology.

哮喘是一种影响全球数百万人的疾病，是一种以气道炎症和气道高反应性为特征的复杂炎症性疾病。虽然多种分子信号和细胞参与哮喘的发病机制，但CD4+ T淋巴细胞已被清楚地证明起着关键作用。特别是以分泌Th2细胞因子为特征的CD4+ T辅助细胞。然而，幼稚T辅助细胞分化为Th2表型的免疫途径尚未明确描述。整合素α e (CD103) β 7在淋巴细胞、树突状细胞和肥大细胞上表达，这些细胞类型与哮喘和粘膜免疫反应的动态调节有关。在以高水平Th2细胞因子、气道高反应性和肺部炎症为特征的小鼠气道高反应性模型中，研究了整合素alphaEbeta7在介导肺部变应性炎症和气道反应性中的作用。研究发现，整合素α e缺陷小鼠的肺部炎症、气道反应性和Th2细胞因子水平明显降低。体外研究表明，来自α e缺陷小鼠的未分离脾细胞产生的Th2细胞因子水平明显低于α e +/+小鼠。混合研究，使用纯化的脾脏CD4+ T细胞群和来自α e缺陷型和野生型小鼠的辅助细胞群，将CD4+ T细胞分化为Th2表型的调节定位到辅助细胞群。考虑到25%的脾脏树突状细胞表达alphaEbeta7，整合素alphaEbeta7在由alphaEbeta7树突状细胞介导的CD4+ T细胞表型发育的调节中起关键作用的假设被提出。为了验证这一假设，将进行体外研究，以证明alphaEbeta7+树突状细胞在CD4+ T细胞向Th2表型分化中的作用，并表征其表型和功能特征。将进行过继性转移实验，以确定alphaEbeta7+树突状细胞在体内介导Th2极化的能力，以及在雾化抗原刺激下赋予气道高反应性和肺部炎症的能力。该整合素在树突状细胞上的表达介导nave T辅助细胞和Th2肺免疫反应分化的机制也将被研究。这些研究可能为整合素在辅助性T细胞分化和树突状细胞生物学中的作用提供重要的见解。