Cockroach and mouse allergy T cell phenotypes and their correlation with clinical status

蟑螂和小鼠过敏 T 细胞表型及其与临床状态的相关性

• 批准号: 10083709
• 负责人: Alessandro Sette
• 金额: $ 41.82万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 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/10083709
• 关键词: 10 year old; 13 year old; Address; Adult; Allergen Immunotherapy; Allergens; Allergic; Allergic Disease; Antigens; Asthma; Biological Assay; Blood; Cell surface; Cells; Cellular Assay; Child; Childhood; Childhood Asthma; Clinical; Data; Development; Dictyoptera; Disease Outcome; Epitope Mapping; Epitopes; Evolution; Exposure to; Extrinsic asthma; Food; Funding; Genetic; Household; Hypersensitivity; Immune; Immune response; Immunologics; Immunophenotyping; Immunotherapy; Individual; Interferon Type II; Interleukin-10; Interleukin-17; Interleukin-5; Investigation; Life; Longitudinal Studies; Measures; Messenger RNA; Monitor; Mus; Nature; Nose; Occupational; Occupations; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Persons; Pertussis; Phenotype; Placebos; Production; Proteins; Proteomics; Sampling; Sampling Studies; Severity of illness; Specificity; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; T-cell receptor repertoire; Tetanus Toxoid; Time; Translating; Validation; Work; clinical phenotype; cockroach allergen; cohort; cytokine; enzyme linked immunospot assay; high risk; immunotherapy clinical trials; immunotherapy trials; inner city; mouse allergen; mouse allergy; novel; protein expression; response; synergism; transcriptome sequencing; urban setting

PROJECT SUMMARY Our proposal focuses on cockroach (CR) and mouse (MO) allergens, dominant in inner city children correlated with development of allergic asthma later on in life. We also rely on epitopes from other allergens and tetanus toxoid (TT) and pertussis (PT) antigens, as important specificity controls. Our studies will answer the RFA question: “Does the presence of T-cells with particular epitope specificities differentiate allergic from non-allergic individuals?” We have already detected significant differences, in both the CR and MO systems, supporting the rationale and feasibility of the proposed work. We will define epitopes with reactivity in non-allergics and allergics with different disease severities. We plan to next answer the questions; “In persons with allergy, do specific T-cell epitopes differentiate between various clinical phenotypes or stages of disease severity? How important is the immunologic phenotype of epitope-specific T-cells as a marker of clinical presentation?” We will study samples taken over time from children from households at high-risk for asthma development. We will count the number of allergen-specific T cells, and define their pattern of protein expression and genetic profiles. Finally, we will ask: “How stable is the epitope-specific T-cell repertoire over time and what are the clinical implications of natural alterations in the repertoire within individuals? Does allergen exposure or AIT influence a particular group of epitope-specific T-cells?” Samples from various donor cohorts will be characterized in terms of number of allergen-specific T cells, protein and genetic profiles. We will study samples from the CoNAC (Cockroach Nasal Allergen Challenge) study, performed by the ICAC network, in sensitized and non-sensitized donors. We will also examine longitudinal samples from an in-house established cohort of donors that are MO non-sensitized but, because of occupational duties, heavily exposed to MO allergens. Finally, we will study longitudinal samples from immunotherapy clinical trials including individuals treated with CR extract or placebo. We will measure the evolution of responses to CR allergens. In addition, we will measure responses to other allergens to which donors are either sensitized or non-sensitized to establish whether immunotherapy only modulates CR responses, or also modulates T cells specific for other allergens.

项目概要 我们的提案重点关注蟑螂 (CR) 和老鼠 (MO) 过敏原，这两种过敏原在市中心儿童中占主导地位 与以后生活中过敏性哮喘的发展相关。我们还依赖于其他表位 过敏原、破伤风类毒素 (TT) 和百日咳 (PT) 抗原，作为重要的特异性对照。我们的 研究将回答 RFA 问题：“具有特定表位的 T 细胞的存在是否存在？ 特异性区分过敏和非过敏个体？”我们已经检测到显着的 CR 和 MO 系统中的差异支持了所提议的基本原理和可行性 工作。我们将定义具有不同疾病的非过敏和过敏反应性的表位 严重程度。我们计划接下来回答问题； “对于过敏体质的人来说，特定的 T 细胞表位 区分各种临床表型或疾病严重程度的阶段？有多重要 表位特异性 T 细胞的免疫表型作为临床表现的标志？”我们将学习 随着时间的推移，从哮喘高危家庭的儿童中采集样本。我们将 计算过敏原特异性 T 细胞的数量，并定义其蛋白质表达模式和 遗传图谱。最后，我们会问：“随着时间的推移，表位特异性 T 细胞库的稳定性如何？ 个体体内曲目的自然改变有何临床意义？做 过敏原暴露或 AIT 会影响一组特定的表位特异性 T 细胞吗？”样品来自 不同的供体群体将根据过敏原特异性 T 细胞、蛋白质和 遗传图谱。我们将研究来自 CoNAC（蟑螂鼻过敏原挑战）研究的样本， 由 ICAC 网络对敏感和非敏感捐助者进行。我们还将检查 来自内部建立的捐赠者队列的纵向样本，这些捐赠者对 MO 不敏感，但是， 由于职业职责，大量接触MO过敏原。最后我们来研究一下纵向 来自免疫治疗临床试验的样本，包括接受 CR 提取物或安慰剂治疗的个体。 我们将测量 CR 过敏原反应的演变。此外，我们将衡量回应 对捐赠者敏感或不敏感的其他过敏原，以确定是否 免疫疗法仅调节 CR 反应，或也调节对其他过敏原具有特异性的 T 细胞。