IMMUNOPATHOGENESIS OF AIRWAY INFLAMMATION

气道炎症的免疫发病机制

• 批准号: 2029421
• 负责人: KIM BOTTOMLY
• 金额: $ 38.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-10 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029421
• 关键词: active immunization; antigen presenting cell; antigens; asthma; cytokine; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; histopathology; immunopathology; inflammation; interleukin 4; laboratory mouse; leukocyte activation /transformation; lung; synthetic nucleic acid; synthetic peptide; tissue /cell culture

Asthma is a disease characterized by reversible airflow obstruction and bronchial inflammation. The goal of this proposal is to understand how environmental antigens influence local immunologic processes in the lung and airways and result in the inflammatory infiltrate and bronchial hyperresponsiveness seen in this disease. There is considerable recent evidence that CD4+ T lymphocytes (Th2 cells) that secrete interleukin-4 and interleukin-5 are involved in the pathogenesis of asthma. These cytokines are associated with airway eosinophilia and high IgE levels that are typically seen in atopic asthmatics. We plan to study airway inflammation and bronchial hyperresponsiveness in the mouse by investigating the role of inhaled antigens in the induction of pulmonary Th2 cells. The induction of Th2 cells during an immune response has been shown to be influenced by three factors: the antigen itself, the type of antigen presenting cell that interacts with the T cell, and the cytokines present at the site of CD4 T cell stimulation. We will use three groups of transgenic mice which will allow us to investigate how each of these factors individually effects Th2 cell induction in the lung and airways. Once we have established conditions that control Th2 dominant responses in the lung, we will examine pulmonary histopathology and measure airway resistance in provoked mice. Thus, we will test our hypothesis that airway hyperresponsiveness and inflammation are associated with selective pulmonary Th2 lymphocyte activation. Further, we will investigate methods to abrogate Th2 responses once they are established. From these studies we hope to gain insight into how the immunologic responses associated with asthma can be manipulated. Overall, we hope to shed light on the complex immunopathogenesis of airway inflammation and its association with bronchial hyperresponsiveness in a transgenic mouse model.

哮喘是一种以可逆性气流阻塞为特征的疾病 支气管炎症。该提案的目标是了解如何 环境抗原影响肺部的局部免疫过程 和气道，导致炎症浸润和支气管 在这种疾病中可见高反应性。最近有相当多的 有证据表明，分泌白细胞介素 4 的 CD4+ T 淋巴细胞（Th2 细胞） 和IL-5参与哮喘的发病机制。这些 细胞因子与气道嗜酸性粒细胞增多和高 IgE 水平相关， 通常见于特应性哮喘患者。我们计划研究气道 小鼠炎症和支气管高反应性 研究吸入抗原在诱导肺部感染中的作用 Th2细胞。 免疫反应过程中 Th2 细胞的诱导已被证明 受三个因素影响：抗原本身、抗原类型 与 T 细胞相互作用的呈递细胞和存在的细胞因子 位于 CD4 T 细胞刺激部位。我们将使用三组 转基因小鼠将使我们能够研究这些小鼠如何 因素单独影响肺和气道中 Th2 细胞的诱导。 一旦我们建立了控制 Th2 主导反应的条件 肺部，我们将检查肺部组织病理学并测量气道 激发小鼠的抵抗力。因此，我们将检验我们的假设，即气道 高反应性和炎症与选择性相关 肺 Th2 淋巴细胞活化。进一步，我们将研究方法 一旦Th2反应建立，就将其废除。从这些研究中我们 希望深入了解免疫反应如何与 哮喘是可以控制的。总的来说，我们希望能够阐明这个复杂的情况 气道炎症的免疫发病机制及其与 转基因小鼠模型中的支气管高反应性。