Role of Th Cell Subsets in Allergic Lung Inflammation

Th 细胞亚群在过敏性肺部炎症中的作用

• 批准号: 6881274
• 负责人: DALE T UMETSU
• 金额: $ 38.01万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881274
• 关键词: CD28 molecule; antigen presentation; asthma; biopsy; bronchomotion; bronchoscopy; cell population study; chemokine; clinical research; cytokine; cytoprotection; flow cytometry; genetically modified animals; immune tolerance /unresponsiveness; inflammation; laboratory mouse; monoclonal antibody; natural killer cells; ovalbumin; phlebotomy; respiratory hypersensitivity; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): The long-term goals of this project are to understand immune regulation of asthma, a serious public health problem that has doubled in prevalence in industrialized countries over the last two decades. We have examined different cell types that are involved in the pathogenesis of and in the protection against asthma, and we now propose to study the role of subsets of NK T cells in these processes. Our focus on NK T cells in asthma is based on striking and novel preliminary data demonstrating that mice deficient in NK T cells do not develop allergen-induced airway hyperresponsiveness (AHR), a cardinal feature of asthma. Thus, neither CD1d knockout nor Ja281 knockout mice sensitized and challenged with ovalbumin, develop AHR. Since NK T cells produce large quantities of cytokines on activation, NK T cells are thought to have a profound influence on the development of immune responses, and therefore we hypothesize that NK T cells in the lungs play a major role in regulating the development of asthma. We will examine the mechanisms by which NK T cells enhance the development of AHR by further examination of Ja281 knockout mice. We will use a model in which BALB/c Jaa281 knockout mice are reconstituted with NK T cells from histocompatible wild type mice or from mice deficient in IL-4, IL-13, IL-10 or costimulatory molecules, isolated with CD1d tetramers and NK T cell specific monoclonal antibodies. These studies will determine the specific cytokines and molecules that NK T cells require for inducing the development of AHR and asthma. In addition, we will determine if subsets of NK T cells, activated to enhance cytolytic activity and IFN-gamma but not IL-4 production, will protect against, rather than enhance, the development of AHR. Finally, we will determine whether NK T cells play a significant role in regulating the development of human asthma by examining the number, distribution and cytokine profiles of NK T cells in the blood and lungs of asthmatic patients and matched control subjects. These studies will ascertain the precise role of NK T cells in the development of asthma, and greatly enhance our understanding of pathogenic and protective mechanisms in asthma.

描述（由申请人提供）：该项目的长期目标是了解哮喘的免疫调节，这是一个严重的公共卫生问题，在过去二十年中工业化国家的患病率翻了一番。我们已经检查了参与哮喘发病机制和预防哮喘的不同细胞类型，现在我们建议研究 NK T 细胞亚群在这些过程中的作用。 我们对哮喘中 NK T 细胞的关注基于引人注目的新颖初步数据，这些数据表明缺乏 NK T 细胞的小鼠不会出现过敏原诱导的气道高反应性 (AHR)，这是哮喘的一个主要特征。因此，CD1d 敲除小鼠和 Ja281 敲除小鼠均不会因卵清蛋白致敏和攻击而发生 AHR。由于 NK T 细胞在激活时会产生大量细胞因子，因此 NK T 细胞被认为对免疫反应的发展具有深远的影响，因此我们假设肺部的 NK T 细胞在调节哮喘的发展中发挥着重要作用。 我们将通过进一步检查 Ja281 敲除小鼠来研究 NK T 细胞增强 AHR 发育的机制。我们将使用一个模型，其中 BALB/c Jaa281 敲除小鼠是用来自组织相容性野生型小鼠或缺乏 IL-4、IL-13、IL-10 或共刺激分子的小鼠的 NK T 细胞重建的，并用 CD1d 四聚体和 NK 分离T 细胞特异性单克隆抗体。这些研究将确定 NK T 细胞诱导 AHR 和哮喘发展所需的特定细胞因子和分子。此外，我们将确定激活以增强细胞溶解活性和 IFN-γ（而非 IL-4 产生）的 NK T 细胞亚群是否会防止而不是增强 AHR 的发展。最后，我们将通过检查哮喘患者和匹配对照受试者血液和肺部中 NK T 细胞的数量、分布和细胞因子谱来确定 NK T 细胞是否在调节人类哮喘的发展中发挥重要作用。 这些研究将确定NK T细胞在哮喘发生发展中的确切作用，并极大地增进我们对哮喘致病和保护机制的理解。