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: 8707948
• 负责人: ANDREW D LUSTER
• 金额: $ 204.55万
• 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/8707948
• 关键词: Affect; Age; Allergens; Allergic; Allergic Disease; Antigens; Asthma; Cell Communication; Cell Count; Cell physiology; Clinical; Dendritic Cell Therapy; Dendritic Cells; Disease; Enrollment; Equilibrium; Extrinsic asthma; Food Hypersensitivity; Foundations; Gene Expression Profile; General Hospitals; Goals; Health; Imaging Techniques; Inflammatory Response; MHC Class II Genes; Massachusetts; Measures; Milk; Mission; Modeling; National Institute of Allergy and Infectious Disease; Outcome; Patients; Phenotype; Physiological; Population; Recruitment Activity; Regulatory T-Lymphocyte; Role; Surface; T-Lymphocyte; T-Lymphocyte Subsets; United States; airway hyperresponsiveness; airway inflammation; disability; innovation; medical schools; novel strategies; novel therapeutic intervention; novel therapeutics; oral immunotherapy; response; trend

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）：马萨诸塞州综合医院/哈佛医学院AADCRC标题为“ T细胞效应子和哮喘和食物过敏的调节机制”，旨在更好地了解过敏原特异性效应子和调节性T细胞在确定对粘膜过敏反应的生理反应中的作用。越来越清楚的是，炎症反应的净结果是过敏原特异性效应T细胞活性和相反的调节T细胞活性的平衡。抗原特异性效应子和调节性T细胞数量和活性在很大程度上取决于过敏原的树突状细胞（DC）与抗原特异性T细胞的相互作用。 MGH/Harvard AADCRC将探索哮喘和食物过敏的效应子和调节活性的平衡，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的任务相关的两种过敏疾病，即过敏性哮喘和食物过敏，并利用两种临床模型[支气管节分段过敏原挑战（SAC）和口服免疫疗法（OIT）]作为研究的基础。项目1的重点是抗原特异性效应子和调节性T细胞在确定气道炎症和气道中的作用，通过使用创新成像技术将这些细胞的数量，表型和功能相关联在过敏性哮喘（AA）和过敏性非ASTHMATICS（AA）中的数量，表型和功能；项目2的重点是将这些相同T细胞子集的数量，表型和功能与正在接受牛奶OIT的牛奶过敏患者的临床结局相关联；项目3的重点是耐受性直流治疗操纵这两个相对的T细胞种群之间平衡的能力，以支持调节性T细胞以及哮喘和食物过敏的耐受性。这三个相互关联的项目将得到核心的支持，这些核心将招募，招募和表征SAC和OIT的过敏主体，为MHC II类四聚体提供特定识别和研究过敏蛋白特异性T细胞，并对T细胞和DC亚群进行复杂的转录组表型分析。该中心的目的是了解效应子和调节性过敏原特异性T细胞活性的平衡，该活性决定哮喘和食物过敏中的临床疾病，并确定使用耐受性DCS操纵这种平衡来诱导过敏原特异性耐受性的实用性。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。