Induction and signature of pathogenic T cells in allergy

描述(由申请人提供)：我们的目标是通过全面了解与过敏性疾病的发病机制和外周对过敏原的耐受性相关的机制，确定用于过敏性疾病的CD4+T细胞特征。研究将在具有不同过敏反应的过敏性个体和非特应性个体中进行。拟议的工作将包括使用新兴技术，包括pMHCII四聚体染色和CD154检测，以跟踪体外过敏原特异性的CD4+T细胞，以及12参数流式细胞术和微阵列转录图谱，以在单细胞水平表征特定的免疫反应。利用这些技术，我们将主要研究与过敏受试者的过敏反应相关的机制。这一信息与了解过敏原特异性TH2细胞的生物学有关，并将提供一个机会来定义反映潜在过敏性疾病过程的特征。了解健康个体中过敏原特异性CD4+T细胞反应的性质对于改进目前的过敏疫苗也是至关重要的，因为假设自然反应对过敏性炎症具有保护作用，因此过敏原特异性免疫治疗应该概括这种免疫反应。我们将最终确定这种过敏T细胞信号可以在多大程度上作为替代生物标记物来评估ASIT的疗效。这项研究将在免疫耐受网络资助的随机双盲、双模拟、对照临床试验(Sit与安慰剂、SCIT与安慰剂)的背景下进行。我们假设：1.变应原特异性TH2细胞代表稳定而独特的TH2细胞亚群(标记为TH2 A亚群)，其定义为CD161表达和CD27缺失。2.非特应性个体的TH_2A细胞群缺失。3.TH2细胞在功能和分子上与传统的TH2细胞不同。4.变应原特异性TH2细胞在SIT过程中具有生存负担。5.过敏性个体的CD27+变应原特异性T细胞反映了对变应原的保护性免疫反应的一些典型特征。6.TH_2A细胞可作为临床有意义的过敏性生物标志物。

DESCRIPTION (provided by applicant): We aim to identify a CD4+ T cell signature for allergic diseases resulting from a comprehensive understanding of the mechanisms associated with the pathogenesis of allergic disease and peripheral tolerance to allergens. Investigations will be performeTd both in allergic individuals with heterogeneous allergic responses and in non- atopic individuals. The proposed work will include the use of emerging technologies including pMHCII tetramer staining and CD154 assay to track the allergen-specific CD4+ T cells ex vivo, together with 12-parameters flow cytometry and microarray transcriptional profiling to characterize specific immune responses at the single cell level. Using these technologies we will primarily investigate mechanisms associated with allergic responses in allergic subjects. This information is pertinent for understanding the biology of allergen-specific TH2 cells and will provide an opportunity to define a signature that reflects an underlying allergic disease process. Understanding the nature of allergen-specific CD4+ T cell responses in healthy individuals is also critical to improve current allergy vaccines, with the assumption that natural responses are protective against allergic inflammation, and thus that allergen-specific immunotherapy should recapitulate such immune responses. We will finally determine the extent to which this allergic T cell signature can be used as a surrogate biomarker to evaluate the efficacy of ASIT. This investigation will be performed in the context of an Immune Tolerance Network funded randomized double-blind, double dummy, controlled clinical trial (SLIT vs. placebo, SCIT vs. placebo). We hypothesize that: 1. Allergen-specific TH2 cells represent a stable and distinct subset of TH2 cells (denoted TH2A subset) defined by CD161 expression and lack of CD27. 2. TH2A cell population is absent in non-atopic individuals. 3. TH2A cells are functionally and molecularly distinct from conventional TH2 cells. 4. Allergen-specific TH2 cells possess a survival burden during SIT. 5. CD27+ allergen-specific T cells from allergic individuals reflect some classic features of the protective immune response to allergens. 6. TH2A cells can be used as a clinically meaningful biomarker in allergies.