Mechanisms of Allergen-induced Type 2 Immunity

过敏原诱导的 2 型免疫机制

• 批准号: 10046475
• 负责人: Hirohito Kita
• 金额: $ 26.51万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 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/10046475
• 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; 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; eosinophilic inflammation; functional genomics; fungus; genetic approach; lymph nodes; microbial; mouse model; novel; novel therapeutics; peripheral blood; prevent; respiratory health; response

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.

项目摘要/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 涉及2型免疫调查的开发 从哮喘到食物过敏的多种疾病。传统上，CD4+ 2型助手T（TH2） 产生白介素（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，例如气道嗜酸性粒细胞和IgE抗体产生。但是，它 仍然无法解决是否仅凭Th2细胞可以解释疾病的临床表型。为了 例如，并非所有患有哮喘的患者开发了对过敏原的IgE抗体，而不是所有可检测的患者 血清IgE抗体水平患哮喘。 T卵泡辅助器（TFH）细胞是CD4+的新定义子集 T细胞通过选择性作用在编排生发中心中与其他T细胞区分开的T细胞 回答。我们在最后一个资金期间的观察结果表明，IL-4产生TFH的角色 调节IgE抗体产生的细胞，但在气道注射中没有表明适应性 实际上，“ 2型免疫”可能至少由两个途径组成。在下一个资金期间，我们将扩展 这些研究并定义了过敏原暴露如何介导的各种免疫学和临床表型 过敏性疾病。在AIM 1中，我们将检查TFH细胞和Th2细胞在过敏性免疫反应中的作用 暴露于天然空气传播原子。我们将利用鼠标模型，并严格定义 这两种细胞类型的作用。在AIM 2中，我们将检查过敏免疫反应中的调节机制 通过关注新确定的T卵泡调节（TFR）细胞。小鼠遗传方法和 对人类的前瞻性研究将用于了解这种新细胞类型的作用。在AIM 3中，我们将 解决了为什么某些环境因素通过研究作为潜在过敏原的基本问题 在过敏性疾病中实施的替代方案。与替代专家克里斯托弗博士合作 劳伦斯，我们将采用强大的真菌功能基因组方法。这些目标的研究将在一起 定义2型免疫对机载的开发和调节的基础机制 过敏原并将提供有关过敏性各种临床表型的免疫学解释 疾病。最终，这些研究将表征与参与有关的关键细胞途径和分子 过敏性免疫反应，允许鉴定出开发新疗法的关键靶标 治疗或预防哮喘和过敏性疾病的策略。