T cell effector and regulatory mechanisms in asthma and food allergy

描述(由申请人提供)：马萨诸塞州综合医院/哈佛医学院AADCRC题为“哮喘和食物过敏中的T细胞效应和调控机制”，旨在更好地了解过敏原特异性效应和调控T细胞在决定粘膜表面对过敏原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性T细胞活性的平衡。抗原特异性效应器和调节性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状细胞(DC)与抗原特异性T细胞相互作用的结果。MGH/哈佛AADCRC将探索哮喘和食物过敏中效应器和调节活动的平衡，以及耐受性DC影响这种平衡的能力。该中心将重点研究与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挑战(SAC)和口服免疫疗法(OIT)]作为其研究的基础。项目1通过使用创新的成像技术将过敏性哮喘患者(AA)和过敏性非哮喘患者(ANA)中这些细胞的数量、表型和功能联系起来，重点研究抗原特异性效应细胞和调节性T细胞在确定呼吸道炎症和呼吸道高反应性中的作用；项目2重点研究这些相同T细胞亚群的数量、表型和功能与接受牛奶燕麦奶过敏患者的临床结果之间的关系；项目3重点研究耐受性DC治疗在哮喘和食物过敏中操纵这两个对立T细胞群之间的平衡的能力，从而有利于调节性T细胞和耐受性。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的过敏性受试者，提供MHC II类四聚体来专门识别和研究过敏原特异性T细胞，并对T细胞和DC亚群进行复杂的转录组表型分析。该中心的目标是了解决定哮喘和食物过敏临床疾病的效应者和调节性变应原特异性T细胞活性的平衡，并建立使用致耐受树突状细胞来操纵这种平衡以诱导变应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。

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.