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

大多数哮喘病例起源于过敏，其特征是嗜酸性气道炎症 与粘液分泌过多和气道高反应性（AHR）相关。气道炎症 哮喘由对来自环境的吸入抗原（过敏原）的过敏型反应引起。现在 很明显，这种反应主要是由CD 4 [+] MHC II类限制性T细胞协调的，这些T细胞识别并 通过它们的T细胞受体被特定的过敏原激活。哮喘表型被认为是 主要由Th 2型CD 4 [+] T细胞驱动;然而，其他CD 4 [+] T细胞亚群，如Th 1细胞，Th 17细胞， 和调节性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类四聚体特异性地鉴定和研究从过敏原中回收的过敏原特异性T细胞。 在人类受试者中支气管内节段性变应原激发（SAC）后的气道和血液中。我们将 比较两组回收的效应T细胞和调节T细胞的数量、表型和功能 过敏性受试者：过敏性哮喘（AA）和过敏性非哮喘（ANA）。由于不明原因，ANA 受试者对皮肤、鼻子和/或眼睛中的常见空气过敏原具有症状性过敏性炎症，但 没有哮喘的症状。我们假设T细胞和淋巴细胞之间 与ANA受试者相比，AA中肺对过敏原的反应，这解释了 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，使用新型和创新的PET-CT进行SAC后气道生理学变化 成像技术。其具体目的是：1）确定气道炎症与 SAC后AHR; 2）确定血液中过敏原特异性和大量CD 4 [+] T细胞的表型 3）为了确定控制SAC中T细胞活化和活性的机制， 检测SAC后气道中T细胞的数量、表型和功能 在SAC之后。这项提案将定义哮喘中T细胞的表型，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。

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.