Epitope validation of fungal allergens in severe asthma

严重哮喘中真菌过敏原的表位验证

基本信息

批准号：
10321625
负责人：
Pandurangan Vijayanand
金额：
$ 34.95万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321625
关键词：
Admission activity Adrenal Cortex Hormones Adult Allergens Allergic Allergic Bronchopulmonary Aspergillosis Alternaria Antigens Aspergillus Aspergillus fumigatus Asthma Automobile Driving Bioinformatics Biological Assay Biological Response Modifier Therapy Bronchiectasis CD4 Positive T Lymphocytes Cattle Cells Cessation of life Child Clinical Cohort Studies Coin Common Epitope Data Set Dictyoptera Enrollment Epitopes Exposure to Failure Food Funding Gene Expression Profile Hospitalization Inflammatory Inhalation Institutes Label Lead Life Milk Molecular Molecular Profiling Mus National Institute of Allergy and Infectious Disease Nature Oral Outcome Pathogenesis Pathogenicity Patients Pertussis Phenotype Play Production Publishing Pyroglyphidae Recruitment Activity Reproduction spores Research Risk Role Sampling Severities Severity of illness Steroid Resistance Steroids Subgroup T cell response T-Lymphocyte TNFSF5 gene Testing Tetanus Th2 Cells Time United States National Institutes of Health Vaccination Validation Visit adverse outcome airway inflammation asthma exacerbation asthmatic asthmatic airway base chemokine cohort cytokine data management genome-wide inner city insight neutrophil pulmonary function response single-cell RNA sequencing transcriptome sequencing transcriptomics validation studies

项目摘要

PROJECT SUMMARY In this application, we will characterize CD4 T cells reactive to epitopes of the fungal allergens Aspergillus fumigatus (ASP) and Alternaria alternata (ALT) to understand the molecular basis of severe asthma. Sensitization and/or exposure to antigens (spores) from fungal species such as ASP and ALT have been strongly associated with risk for a number of asthma-severity-related adverse outcomes. Based on this premise, we will test the hypotheses that (i) Fungal allergen-specific CD4 T cells are more pathogenic and qualitatively different when compared to allergen-specific CD4 T cells directed towards non-fungal inhaled allergens such as house dust mite (HDM), cockroach (CR), mouse (MO) or potential oral allergens such as cow milk (CM). (ii) Fungal allergen-epitope-specific CD4 T cells in patients with severe asthma have more pathogenic features than those from mild asthmatics. We will capitalize on subjects enrolled in three large asthma cohorts for these studies. In Aim 1, we will define epitopes recognized by Aspergillus (ASP) and Alternaria (ALT)-sensitized asthmatics categorized based on disease severity. The reactivity of predicted ASP and ALT epitopes will be tested in 20 sensitized subjects with mild and severe asthma and in 20 non-sensitized subjects without asthma to assess the nature of allergic versus healthy responses. By comparing the epitope-reactivity of the three cohorts, we will define epitopes that are common or specific to each subgroup: severe asthma, mild asthma and non- sensitized non-asthmatics. In Aim 2, we will determine the molecular profile of fungal (ASP and ALT)-specific CD4 T cells in patients with different asthma severity. We will utilize fungal epitope mega-pools to define the phenotype and transcriptional profile (at bulk and single-cell level) of ASP and ALT epitope-specific CD4 T cell responses in 10-20 fungal-sensitized subjects with severe and mild-to-moderate asthma, allergic bronchopulmonary aspergillosis (ABPA) and in control subjects without asthma. In parallel, we will also assess the molecular profile of fungal-specific CD4 T cells present in the airways of asthmatic subjects. To determine if the molecular features of fungal allergen-specific CD4 T cells are different from allergen-specific CD4 T cells directed to HDM, CR, MO, CM or antigen-specific Th2 cells induced by vaccination (pertussis and tetanus), we will perform additional transcriptomic analysis of these cells, and through the integrated Data Management Core specializing in bioinformatics cross compare data sets with Project 1 and 2. Together these fungal epitope validation studies in subjects with varying asthma severity will provide insights into the nature of CD4 T cell responses that drive pathogenesis of severe asthma.

项目摘要在此应用中，我们将表征CD4 T细胞对真菌过敏原曲霉的表位的反应 Fumigatus（ASP）和Alternaria Alternata（ALT）了解严重哮喘的分子基础。来自ASP和ALT等真菌物种的敏化和/或暴露于抗原（孢子）已是与许多与哮喘相关的不良后果的风险密切相关。基于此前提，我们将测试（i）真菌过敏原特异性CD4 T细胞更具致病性和与针对非腐蚀吸入的过敏原特异性CD4 T细胞相比，定性不同过敏原，例如房屋尘螨（HDM），蟑螂（CR），鼠标（MO）或潜在的口服过敏原，例如牛奶（CM）。（ii）严重哮喘患者的真菌过敏原特异性CD4 T细胞具有更多致病特征比轻度哮喘患者。我们将利用参加三个大型的主题这些研究的哮喘队列。在AIM 1中，我们将定义曲霉（ASP）和替代（ALT）敏感哮喘患者认可的表位根据疾病的严重程度进行分类。预测的ASP和ALT表位的反应性将在20中测试具有轻度和严重哮喘的敏化受试者以及20名没有哮喘的非敏化受试者以评估过敏反应与健康反应的性质。通过比较三个队列的表位反应性，我们将定义每个亚组常见或特定的表位：严重哮喘，轻度哮喘和非 - 敏化的非asthmatics。在AIM 2中，我们将确定真菌（ASP和ALT）特异性的分子曲线患有不同哮喘严重程度的患者的CD4 T细胞。我们将利用真菌表位巨型池定义 ASP和Alt表位特异性CD4 T细胞的表型和转录曲线（在批量和单细胞水平上） 10-20个真菌敏感受试者的反应，严重和轻度至中度哮喘过敏支气管肺曲霉病（ABPA）和没有哮喘的对照受试者。同时，我们还将评估真菌特异性CD4 T细胞的分子谱存在于哮喘受试者的气道中。确定是否真菌过敏原特异性CD4 T细胞的分子特征与过敏原特异性CD4 T细胞不同我们针对HDM，CR，MO，CM或抗原特异性TH2细胞，疫苗接种（百日咳和破伤风），我们将对这些单元格进行其他转录组分析，并通过集成数据管理执行专门研究生物信息学交叉将数据集与项目1和2进行比较。哮喘严重程度变化的受试者的表位验证研究将为CD4 T的性质提供见解驱动严重哮喘发病机理的细胞反应。