Mechanisms of Allergen-induced Type 2 Immunity

过敏原诱导的 2 型免疫机制

基本信息

批准号：
10182141
负责人：
Hirohito Kita
金额：
$ 40.92万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10182141
关键词：
Address Allergens Allergic Allergic Disease Alternaria Ambrosia Antibodies Antibody Formation Antigens Asthma Biological CD4 Positive T Lymphocytes Cell physiology Cells Collaborations Data Development Disease Environmental Risk Factor Eosinophilia Epithelial Epithelium Exposure to Food Hypersensitivity Functional disorder Funding Genes Genomic approach Grant Hay fever Helper-Inducer T-Lymphocyte Heterogeneity Human IgE Immune Immune response Immunity Immunologics Inhalation Interleukin-13 Interleukin-4 Interleukin-5 Interleukins Mediating Mucous Membrane Mus Outcome Pathology Pathway interactions Patients Phenotype Play Production Prospective Studies Recombinant Proteins Regulation Role Serum Structure of germinal center of lymph node T-Lymphocyte TSLP gene Testing airborne allergen airway inflammation arm base beta-Galactosidase cell type clinical phenotype cytokine disease phenotype draining lymph node eosinophilic inflammation functional genomics fungus genetic approach microbial mouse genetics mouse model novel novel therapeutics peripheral blood prevent respiratory health response

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term objective of this grant is to investigate how airway exposure to natural allergens leads to development of type 2 immunity and allergic diseases. Exaggerated type 2 immune responses are implicated in a wide variety of disorders ranging from asthma to food allergy. Traditionally, CD4+ type 2 helper T (Th2) cells that produce interleukin (IL)-4, IL-5, and IL-13 have been considered major players in directing the pathophysiology of these diseases, such as airway eosinophilia and IgE antibody production. However, it remains unresolved whether Th2 cells alone can explain the spectrum of clinical phenotypes of disease. For example, not all patients with asthma develop IgE antibodies to allergens, and not all patients with detectable serum IgE antibody levels develop asthma. T follicular helper (Tfh) cells are a newly defined subset of CD4+ T cells that are distinguished from other T cells by their selective role in orchestrating germinal center responses. Our observations during the last funding period demonstrate a pivotal role for IL-4-producing Tfh cells in the regulation of IgE antibody production, but not in airway inflammation, suggesting that adaptive “type 2 immunity” may in fact consist of at least two pathways. In the next funding period, we will extend these studies and define how allergen exposure mediates various immunologic and clinical phenotypes of allergic diseases. In Aim 1, we will examine the roles of Tfh cells and Th2 cells in allergic immune responses induced by exposure to natural airborne allergens. We will leverage mouse models and critically define the roles of these two cell types. In Aim 2, we will examine regulatory mechanisms in allergic immune responses by focusing on newly identified T follicular regulatory (Tfr) cells. Both a mouse genetic approach and a prospective study in humans will be used to understand the roles of this new cell type. In Aim 3, we will address the fundamental question of why certain environmental factors serve as potent allergens by studying Alternaria, which is implicated in allergic diseases. In collaboration with an Alternaria expert, Dr. Christopher Lawrence, we will take a robust fungal functional genomic approach. Together, the studies in these aims will define the central mechanisms underlying the development and regulation of type 2 immunity to airborne allergens and will provide an immunologic explanation regarding various clinical phenotypes of allergic diseases. Ultimately, these studies will characterize key cellular pathway(s) and molecule(s) involved in allergic immune responses, allowing identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and allergic diseases.

项目概要/摘要这笔赠款的长期目标是调查气道暴露于天然过敏原如何导致 2 型免疫的发展和过敏性疾病有关。2 型免疫反应过度。传统上，CD4+ 2 型辅助性 T (Th2) 疾病可用于治疗从哮喘到食物过敏等多种疾病。产生白细胞介素 (IL)-4、IL-5 和 IL-13 的细胞被认为是指导这些疾病的病理生理学，例如气道嗜酸性粒细胞增多和 IgE 抗体的产生。 Th2 细胞是否可以单独解释疾病的临床表型谱仍是一个悬而未决的问题。例如，并非所有哮喘患者都会产生针对过敏原的 IgE 抗体，也并非所有可检测到过敏原的患者都会产生 IgE 抗体。血清 IgE 抗体水平会导致哮喘。滤泡辅助 T (Tfh) 细胞是新定义的 CD4+ 子集。 T 细胞与其他 T 细胞的区别在于其在协调生发中心中的选择性作用我们在上一个资助期间的观察结果表明，产生 IL-4 的 Tfh 发挥着关键作用。细胞参与 IgE 抗体产生的调节，但不参与气道炎症，这表明适应性 “2型免疫”实际上可能至少包含两种途径，在下一个资助期内，我们将延长资助期限。这些研究并定义了过敏原暴露如何介导各种免疫学和临床表型在目标 1 中，我们将研究 Tfh 细胞和 Th2 细胞在过敏性免疫反应中的作用。由暴露于天然空气传播的过敏原引起的。我们将利用小鼠模型并严格定义。在目标 2 中，我们将研究过敏性免疫反应的调节机制。通过关注新发现的滤泡调节 T (Tfr) 细胞，既采用小鼠遗传方法，又采用小鼠遗传方法。在目标 3 中，我们将利用人类前瞻性研究来了解这种新细胞类型的作用。通过研究解决为什么某些环境因素成为有效过敏原的基本问题链格孢菌，与过敏性疾病有关。与链格孢菌专家 Christopher 博士合作。劳伦斯，我们将共同采取强大的真菌功能基因组方法，以实现这些目标的研究。定义对空气传播的 2 型免疫的发展和调节的核心机制过敏原，并将提供有关过敏的各种临床表型的免疫学解释最终，这些研究将描述参与疾病的关键细胞途径和分子。过敏性免疫反应，可以识别开发新疗法的关键靶点治疗或预防哮喘和过敏性疾病的策略。