Analysis of Fel d 1-specific T cells after airway allergen challenge in asthma

哮喘气道过敏原激发后 Fel d 1 特异性 T 细胞分析

• 批准号: 8651876
• 负责人: Gail M Gauvreau
• 金额: $ 49.37万
• 依托单位: MCMASTER UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8651876
• 关键词: Allergens; Asthma; Blood; Blood specimen; Bone Marrow; Breathing; Bronchial Provocation Tests; CC chemokine receptor 4; CCL17 gene; CCL22 gene; CXCL12 gene; CXCR4 gene; Cells; Clinical; Clinical Trials; Dendritic Cells; Development; Disease; Eosinophilia; Epitopes; Felis catus; Frequencies; Goals; HLA-DR Antigens; HLA-DR4 Antigen; Hour; Human; Hypersensitivity; Immune system; Immunotherapy; Instruction; Laboratories; Ligands; Lung; MHC Class II Genes; Maintenance; Measures; Methodology; Modeling; Mus; Obstruction; Pathogenesis; Peptides; Phenotype; Public Health; Reaction; Reagent; Risk Factors; Spleen; Stromal Cell-Derived Factor 1; Structure of parenchyma of lung; T-Lymphocyte; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Vaccines; airway hyperresponsiveness; airway inflammation; allergic airway disease; chemokine receptor; eosinophil; improved; lymph nodes; peripheral blood; prevent; response; trafficking

PROJECT SUMIVIARY (See instructions): Allergen inhalation by atopic asthmatics in the laboratory results in most of the manifestations of asthma, including reversible airflow obstruction, AHR and airway inflammation. This methodology has been used to examine the mechanisms of eosinophil, T-cell, and dendritic cell trafficking to/from the bone marrow to/from the blood and to the airways. The current proposal will capitalize on the unique opportunity offered by this allergen-specific model of direct bronchial challenge, by using MHC class II allergen tetramer reagents to enrich and characterize, ex vivo, Fel d 1 epitope-specific T cells before and after a localized bronchial allergen challenge. The overarching hypothesis of this proposal is that trafficking of allergen-specific T cells (tetramer+) from the blood to the airways and bone marrow is associated with the development of the late asthmatic reaction. This study will measure the frequency of Fel d 1-specific T cells, how these cells traffic between relevant compartments (blood, bone marrow and airways) and how their functional phenotype changes in response to allergen challenge. The specific aims of this proposal are: Aim 1: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the blood and the airways following lung segmental allergen challenge. Aim 2: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the bone marrow following lung segmental allergen challenge. Aim 3: To determine the frequency and functional phenotype of Fel d 1-specific (Fel d 1 MHC class II tetramer+) T cells in the blood, the airways (BAL and digested lung tissue), the lymph nodes draining the airways, the spleen and the bone marrow following inhaled allergen challenge in an HLA-DR4-transgenic murine model of allergic airways disease, and to assess the effects of peptide immunotherapy, using components of a human vaccine currently in clinical trials, on these parameters. The results of these studies will help to clarify how allergen-specific T cells contribution to the pathogenesis of asthma and inform development of rational approaches to therapeutic intervention.

项目概要（见说明）： 过敏性哮喘患者在实验室中吸入过敏原导致哮喘的大多数表现，包括可逆性气流阻塞、AHR和气道炎症。该方法已被用于检查嗜酸性粒细胞、T细胞和树突状细胞从骨髓到骨髓/从骨髓到骨髓的运输机制。 血液和呼吸道目前的建议将利用这种过敏原特异性模型提供的独特的机会，直接支气管的挑战，通过使用MHC II类过敏原四聚体试剂富集和表征，离体，Fel d 1表位特异性T细胞之前和之后的局部支气管过敏原的挑战。该提议的首要假设是，过敏原特异性T细胞的运输 （四聚体+）从血液进入气道和骨髓与晚期哮喘反应的发展有关。这项研究将测量Fel d 1特异性T细胞的频率，这些细胞如何在相关隔室（血液，骨髓和气道）之间运输，以及它们的功能表型如何响应过敏原挑战而变化。这项建议的具体目标是： 目标1：确定肺节段性变应原激发后血液和气道中Fel d 1特异性（Fel d 1 MHC II类四聚体+）T细胞的频率和功能表型。 目标二：确定肺节段性变应原激发后骨髓中Fel d 1特异性（Fel d 1 MHC II类四聚体+）T细胞的频率和功能表型。 目标三：为了确定Fel d 1特异性表达的频率和功能表型，（Fel d 1 MHC II类四聚体+）血液、气道中的T细胞在过敏性气道疾病的HLA-DR 4转基因鼠模型中，在吸入过敏原攻击后，对肺组织（BAL和消化的肺组织）、引流气道的淋巴结、脾和骨髓进行免疫学检查，并评估肽免疫疗法的作用，使用目前在临床试验中的人类疫苗的成分，在这些参数上。 这些研究的结果将有助于阐明过敏原特异性T细胞如何参与哮喘的发病机制，并为合理的治疗干预方法的发展提供信息。