Linking allergen-specific T cell effector and regulatory responses to asthma

将过敏原特异性 T 细胞效应器与哮喘调节反应联系起来

• 批准号: 8196484
• 负责人: ANDREW D LUSTER
• 金额: $ 35.51万
• 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/8196484
• 关键词: Accounting; Allergens; Allergic; Allergic inflammation; Antigens; Asthma; Blood; Breathing; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic Disease; Clinical; Data; Environment; Extrinsic asthma; Eye; Food; Food Hypersensitivity; Frequencies; Generations; Goals; Health Care Costs; Hour; Human; Imaging Techniques; Inflammation; Inflammatory; Inflammatory Response; Link; Lung; MHC Class II Genes; Measures; Mediating; Modeling; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Mus; Nature; Nose; Obstruction; Pathogenesis; Phenotype; Physiological; Physiology; Population; Population Study; Positron-Emission Tomography; Prevalence; Production; Proteins; Reaction; Recruitment Activity; Regulatory T-Lymphocyte; Relative (related person); Skin; Source; Symptoms; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Time; airborne allergen; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; data sharing; human subject; innovation; new therapeutic target; novel; oral immunotherapy; response; standard measure

Most cases of asthma are allergic in origin and are characterized by eosinophilic airway inflammation associated with mucous hypersecretion and airways hyper-responsiveness (AHR). Airway inflammation in asthma results from an allergic-type reaction to an inhaled antigen (allergen) from the environment. It is now clear that this reaction is primarily orchestrated by CD4[+] MHC class II restricted T cells that recognize and become activated by specific allergens via their T cell receptor. The asthma phenotype is thought to be primarily driven by Th2-type CD4[+] T cells; however, other CD4[+] T cell subsets, such as Th1 cells, Th17 cells and regulatory T cells (Tregs) have also been implicated in asthma pathogenesis. In this proposal, we will use MHC class II tetramers to specifically identify and study allergen-specific T cells recovered from the airways and blood following endobronchial segmental allergen challenge (SAC) in human subjects. We will compare the numbers, phenotype and function of effector and regularoty T cells recovered from two groups of allergic subjects: allergic asthmatics (AA) and allergic non-asthmatics (ANA). For unclear reasons, ANA subjects have symptomatic allergic inflammation to common aeroallergens in the skin, nose and/or eyes, but do not have symptoms of asthma. We hypothesize that there are fundamental differences in the T cell response in the lung to allergens in AA when compared to ANA subjects that account for the difference in the clinical response. In this project we will correlate the phenotypic and functioanl differences in T cell subtypes in these subjects to changes in airway physiology following SAC utilizing novel and innovative PET-CT imaging techniques. The specific aims are: 1) To determine the correlation between airway inflammation and AHR following SAC; 2) To determine the phenotype of allergen-specific and bulk CD4[+] T cells in the blood and airway following SAC; 3) To identify the mechanisms that control T cell activation and activity in the airways following SAC; 4) To determine the numbers, phenotype and function of Tregs in the airway following SAC. This proposal will define the phenotype of T cells in asthma, the mechanisms that control their activity, and the links between allergic airway inflammation and AHR.

大多数哮喘病例起源于过敏，其特征是嗜酸粒细胞性气道炎症 与粘液分泌过多和气道高反应性（AHR）有关。气道炎症 哮喘是由对环境中吸入的抗原（过敏原）的过敏反应引起的。现在是 显然，该反应主要由 CD4[+] MHC II 类限制性 T 细胞精心策划，这些 T 细胞识别和 通过 T 细胞受体被特定过敏原激活。哮喘表型被认为是 主要由 Th2 型 CD4[+] T 细胞驱动；然而，其他 CD4[+] T 细胞亚群，例如 Th1 细胞、Th17 细胞 调节性 T 细胞 (Treg) 也与哮喘发病机制有关。在本提案中，我们将 使用 MHC II 类四聚体来特异性识别和研究从 人类受试者支气管内节段性过敏原激发（SAC）后的气道和血液。我们将 比较两组中回收的效应 T 细胞和规则 T 细胞的数量、表型和功能 过敏受试者：过敏性哮喘患者（AA）和过敏性非哮喘患者（ANA）。由于不明原因，ANA 受试者对皮肤、鼻子和/或眼睛中常见的空气过敏原有症状的过敏性炎症，但是 没有哮喘症状。我们假设 T 细胞存在根本差异 与 ANA 受试者相比，AA 受试者肺部对过敏原的反应，这解释了 AA 受试者的差异 临床反应。在这个项目中，我们将关联 T 细胞亚型的表型和功能差异 利用新颖和创新的 PET-CT 在这些受试者中观察 SAC 后气道生理学的变化 成像技术。具体目标是： 1）确定气道炎症与 SAC 之后的 AHR； 2) 确定血液中过敏原特异性和大量 CD4[+] T 细胞的表型 和 SAC 后的气道； 3) 确定控制 T 细胞活化和活性的机制 遵循 SAC 的航空公司； 4) 确定气道中Tregs的数量、表型和功能 遵循 SAC。该提案将定义哮喘中 T 细胞的表型以及控制哮喘的机制 它们的活性，以及​​过敏性气道炎症和 AHR 之间的联系。