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: 6191503
• 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/6191503
• 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。 尽管多种分子信号和细胞参与哮喘的发病机制，但 CD4+ T 淋巴细胞已被明确证明发挥着关键作用。 具体来说，CD4+ T 辅助细胞的特点是分泌 Th2 细胞因子。 然而，幼稚 T 辅助细胞分化为 Th2 表型的免疫途径尚未明确。 整合素 alphaE(CD103)beta7 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。 在气道高反应性体内小鼠模型中研究了整合素αEβ7在介导肺部过敏性炎症和气道反应性中的作用，该模型的特征是高水平的Th2细胞因子、气道高反应性和肺部炎症。 研究发现，整合素 αE 缺陷小鼠的肺部炎症、气道反应性降低，并且 Th2 细胞因子水平显着降低。 体外研究表明，来自 alphaE 缺陷小鼠的未分级脾细胞产生的 Th2 细胞因子水平显着低于 alphaE+/+ 小鼠。使用来自 alphaE 缺陷型和野生型小鼠的纯化脾 CD4+ T 细胞和辅助细胞群进行混合研究，将 CD4+ T 细胞分化为辅助细胞群的 Th2 表型的调节局部化。 鉴于 alphaEbeta7 在 25% 的脾树突状细胞上表达，因此提出了这样的假设：整合素 alphaEbeta7 在调节由 alphaEbeta7 树突状细胞介导的 CD4+ T 细胞表型发育中发挥着关键作用。为了检验这一假设，将进行体外研究以证明 alphaEbeta7+ 树突状细胞在 CD4+ T 细胞分化为 Th2 表型中的作用，并表征其表型和功能特征。将进行过继转移实验以确定αEβ7+树突细胞在体内介导Th2极化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。 树突状细胞上的整合素表达介导幼稚 T 辅助细胞分化和 Th2 肺部免疫反应的机制也将得到研究。这些研究可能为整合素 alphaEbeta7 在 T 辅助细胞分化和树突状细胞生物学中的作用提供重要见解。