T cell effector and regulatory mechanisms in asthma and food allergy

哮喘和食物过敏中的 T 细胞效应和调节机制

• 批准号: 8165321
• 负责人: ANDREW D LUSTER
• 金额: $ 203.96万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165321
• 关键词: cell; effector; regulatory; mechanisms; asthma

DESCRIPTION (provided by applicant): The Massachusetts General Hospital/Harvard Medical School AADCRC entitled "T cell effector and regulatory mechanisms in asthma and food allergy" seeks to gain a better understanding of the role of allergen-specific effector and regulatory T cells in determining the physiological response to an allergen at mucosal surfaces. It is becoming increasingly clear that the net outcome of an inflammatory response is the balance of allergen-specific effector T cell activity and opposing regulatory T cell activity. Antigen-specific effector and regulatory T cell numbers and activity are in large measure determined by the outcome of allergen-loaded dendritic cell (DC) interactions with antigen-specific T cells. The MGH/Harvard AADCRC will explore the balance of effector and regulatory activity in asthma and food allergy and the ability of tolerogenic DCs to affect this balance. The Center will focus on two allergic conditions relevant to the mission of the NIAID, namely allergic asthma and food allergy, and utilize two clinical models [endobronchial segmental allergen challenge (SAC) and oral immunotherapy (OIT)] as a foundation for its studies. Project 1 focuses on the role of antigen-specific effector and regulatory T cells in determining airways inflammation and airways hyper-reactivity by correlating the numbers, phenotype and function of these cells in allergic asthmatics (AA) and allergic nonasthmatics (ANA) using innovative imaging techniques; Project 2 focuses on correlating the numbers, phenotype and function of these same T cell subsets with clinical outcomes of milk allergic patients undergoing milk OIT; and Project 3 focuses on the ability of tolerogenic DC therapy to manipulate the balance between these two opposing T cell populations in favor of regulatory T cells and tolerance in both asthma and food allergy. The three interrelated projects will be supported by Cores that will recruit, enroll and characterize allergic subjects for SAC and OIT, provide MHC class II tetramers to specifically identify and study allergen-specific T cells, and perform sophisticated transcriptome phenotypic analysis on T cell and DC subsets. The goal of this Center is to understand the balance of effector and regulatory allergen-specific T cell activity that determines clinical disease in asthma and food allergy and to establish the utility of using tolerogenic DCs to manipulate this balance to induce allergen-specific tolerance. This would pave the way for new therapeutic approaches to treat these and other allergic diseases.

描述（由申请人提供）：马萨诸塞州总医院/哈佛医学院 AADCRC 题为“哮喘和食物过敏中的 T 细胞效应器和调节机制”，旨在更好地了解过敏原特异性效应器和调节性 T 细胞在确定过敏原中的作用。粘膜表面对过敏原的生理反应。越来越清楚的是，炎症反应的最终结果是过敏原特异性效应 T 细胞活性和相反的调节性 T 细胞活性的平衡。抗原特异性效应细胞和调节性 T 细胞的数量和活性在很大程度上取决于负载过敏原的树突细胞 (DC) 与抗原特异性 T 细胞相互作用的结果。 MGH/哈佛大学 AADCRC 将探索哮喘和食物过敏中效应器和调节活性的平衡，以及耐受性 DC 影响这种平衡的能力。该中心将重点关注与NIAID使命相关的两种过敏性疾病，即过敏性哮喘和食物过敏，并利用两种临床模型[支气管内节段性过敏原激发（SAC）和口服免疫疗法（OIT）]作为其研究的基础。项目 1 重点研究抗原特异性效应细胞和调节性 T 细胞在确定气道炎症和气道高反应性中的作用，方法是使用创新成像技术关联过敏性哮喘 (AA) 和过敏性非哮喘 (ANA) 中这些细胞的数量、表型和功能技术；项目 2 侧重于将这些相同 T 细胞亚群的数量、表型和功能与接受牛奶 OIT 的牛奶过敏患者的临床结果相关联；项目 3 重点关注致耐受性 DC 疗法操纵这两种相反 T 细胞群之间的平衡，有利于调节性 T 细胞以及哮喘和食物过敏的耐受性的能力。这三个相互关联的项目将得到 Cores 的支持，Cores 将为 SAC 和 OIT 招募、登记和表征过敏受试者，提供 MHC II 类四聚体以专门识别和研究过敏原特异性 T 细胞，并对 T 细胞和 DC 进行复杂的转录组表型分析子集。该中心的目标是了解决定哮喘和食物过敏临床疾病的效应器和调节性过敏原特异性 T 细胞活性的平衡，并建立使用致耐受 DC 来操纵这种平衡以诱导过敏原特异性耐受的效用。这将为治疗这些和其他过敏性疾病的新治疗方法铺平道路。