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

大多数哮喘患者都是过敏性哮喘，以嗜酸性呼吸道炎症为特征。 与粘液高分泌和呼吸道高反应性(AHR)相关。呼吸道炎症在中国 哮喘是由环境中吸入的抗原(过敏原)引起的过敏性反应所致。现在是时候了 明确这一反应主要是由CD4[+]MHC II类限制性T细胞识别和 通过它们的T细胞受体被特定的过敏原激活。哮喘的表型被认为是 主要由Th2型CD4[+]T细胞驱动；然而，其他CD4[+]T细胞亚群，如Th1细胞、Th17细胞 调节性T细胞(Tregs)也参与了哮喘的发病机制。在这项提案中，我们将 使用MHC II类四聚体特异性识别和研究从 受试者支气管腔内节段性变应原激发(SAC)后的呼吸道和血液。我们会 两组回收的效应性和调节性T细胞的数量、表型和功能的比较 过敏性受试者：过敏性哮喘(AA)和过敏性非哮喘(ANA)。原因不明，全日空 受试者对皮肤、鼻子和/或眼睛中常见的空气过敏原有症状性过敏性炎症，但 没有哮喘的症状。我们假设T细胞之间有根本的不同 与ANA受试者相比，AA受试者肺对变应原的反应 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 在这些受试者中使用新颖和创新的PET-CT来观察SAC后呼吸道生理的变化 成像技术。具体目的是：1)确定呼吸道炎症和 SAC后的AHR；2)确定血液中变应原特异的和大量的CD4[+]T细胞的表型 和SAC后的呼吸道；3)确定控制T细胞活化和活性的机制 4)测定气道中树突状细胞的数量、表型和功能 在SAC之后。这一提议将定义哮喘中T细胞的表型，即控制哮喘的机制 它们的活性，以及过敏性呼吸道炎症和AHR之间的联系。

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.