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: 6774790
• 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/6774790
• 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.

哮喘是一种以气道炎症和气道高反应性为特征的复杂炎症性疾病，在全世界影响数百万人。 虽然哮喘的发病机制涉及多种分子信号和细胞，但CD 4 + T淋巴细胞已被明确显示起关键作用。 具体地，CD 4 + T辅助细胞的特征在于分泌Th 2细胞因子。 然而，幼稚T辅助细胞分化为Th 2表型的免疫学途径尚未被清楚地描述。 整合素α E（CD 103）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应答的动态调节有关。 在气道高反应性的体内鼠模型中研究了整联蛋白α E β 7在肺变应性炎症和气道反应性的介导中的作用，所述气道高反应性的特征在于高水平的Th 2细胞因子、气道高反应性和肺炎症。 发现整合素α E缺陷小鼠具有降低的肺部炎症、气道反应性和显著降低的Th 2细胞因子水平。 体外研究表明，与alphaE+/+小鼠相比，来自alphaE缺陷小鼠的未分级脾细胞产生显著更低水平的Th 2细胞因子。混合研究，使用纯化的脾CD 4 + T细胞和辅助细胞从alphaE缺陷型和野生型小鼠，定位调节CD 4 + T细胞分化为辅助细胞群体的Th 2表型。 鉴于25%的脾树突状细胞表达α Ebeta 7，提出了整合素α Ebeta 7在α Ebeta 7树突状细胞介导的CD 4 + T细胞表型发育调节中起关键作用的假设。为了检验这一假设，将进行体外研究以证明α E β 7+树突状细胞在CD 4 + T细胞分化为Th 2表型中的作用，并表征其表型和功能特征。将进行连续转移实验以确定α E β 7+树突细胞在体内介导Th 2极化的能力以及响应于雾化抗原攻击而赋予气道高反应性和肺部炎症的能力。 树突状细胞表达整合素介导NA分化的机制还将检查T辅助细胞和Th 2肺免疫应答。这些研究可能为整合素α E β 7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。