Mechanisms of Allergen-induced Type 2 Immunity

过敏原诱导的 2 型免疫机制

• 批准号: 10516908
• 负责人: Hirohito Kita
• 金额: $ 59.57万
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516908
• 关键词: Acute; Allergens; Allergic; Allergic Disease; Alternaria; Anaphylaxis; Antibodies; Antibody Formation; Asthma; Award; Cells; Collaborations; Data; Development; Disease; Eosinophilia; Exposure to; Food Hypersensitivity; Functional disorder; Funding; Galactosidase; Genomic approach; Grant; Helper-Inducer T-Lymphocyte; IgE; Immune response; Immunity; Immunologics; Inflammation; Inhalation; Instruction; Interleukin-13; Interleukin-4; Interleukin-5; Kale - dietary; Lung; Manuscripts; Mediating; Memory; Mucous Membrane; Mus; Parabiosis; Pathway interactions; Patients; Play; Production; Progress Reports; Regulation; Respiratory Mucosa; Role; Tissues; airborne allergen; cell type; clinical phenotype; cytokine; eosinophilic inflammation; functional genomics; fungus; genetic approach; mouse genetics; mouse model; novel therapeutic intervention; prevent; programmed cell death protein 1; respiratory health

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. During the previous funding period of this MERIT Award, we have made major progress in all three Aims. We found that allergen- specific T follicular helper (Tfh) cells and tissue-resident memory (Trm) cells play distinct roles in allergic immune responses. Specifically, Tfh cells promoted production of allergen-specific IgE antibodies and development of acute anaphylaxis while Th2-type Trm cells likely play a role in allergen-induce type 2 cytokine production and eosinophilic inflammation in mucosal tissues. Here we request a 5-year extension of the MERIT Award to continue studying the immunologic mechanism of type 2 immunity. We will finalize and submit at least 4 manuscripts that are described in the progress report. We will extend the studies of the previous funding period and define how allergen exposure mediates various immunologic and clinical phenotypes of allergic diseases. In Aim 1, we will examine the the roles of Th2-type Trm cells in mediating type 2 cytokine production and eosinophilic inflammation in airway mucosa. We will leverage mouse models and use parabiosis and immunologic and genetic approaches to critically define the functions of Trm cells and their regulatory mechanisms. In Aim 2, we will examine how lung T resident helper (Trh) cells mediate IgE antibody production and inflammation in mucosal tissues. Our preliminarily data show the presence of CD4+PD-1+FR4+ Trh cells, a new subset of Tfh-like cells, in the lungs of mice exposed to allergens. We will use mouse genetic approaches to characterize this new cell type and understand its roles in type 2 immunity. In Aim 3, we continue collaborating with Dr. Shiv Kale, and ask a fundamental question why certain allergens robustly induce type 2 immunity. We will take a fungal functional genomic approach and study the roles of - galactosidases produced by fungus Alternaria. 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. RELEVANCE (See instructions): Patients with asthma and allergic diseases have persistent respiratory health problems and exaggerated immune responses to common inhaled allergens. This project will investigate how exposure to natural allergens causes, prolongs, and intensifies these diseases.

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型免疫和过敏性疾病的发展。夸大的 2 型免疫反应与 从哮喘到食物过敏等多种疾病。传统上，CD4+ 2 型辅助 T (Th2) 细胞 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。此前期间 在本次优异奖的资助期间，我们在所有三个目标方面都取得了重大进展。我们发现过敏原—— 特异性滤泡辅助 T (Tfh) 细胞和组织驻留记忆 (Trm) 细胞在过敏性免疫中发挥不同作用 回应。具体来说，Tfh 细胞促进过敏原特异性 IgE 抗体的产生和 急性过敏反应，而 Th2 型 Trm 细胞可能在过敏原诱导的 2 型细胞因子产生中发挥作用， 粘膜组织中的嗜酸性炎症。在此，我们请求将优异奖延长 5 年 继续研究2型免疫的免疫机制。我们将最终确定并提交至少 4 个 进度报告中描述的手稿。我们将延长上一个资助期的研究 并定义过敏原暴露如何介导过敏性疾病的各种免疫学和临床表型。在 目标 1，我们将研究 Th2 型 Trm 细胞在介导 2 型细胞因子产生和 气道粘膜嗜酸性粒细胞炎症。我们将利用小鼠模型并使用联体共生和 免疫学和遗传学方法严格定义 Trm 细胞的功能及其调节 机制。在目标 2 中，我们将研究肺 T 辅助细胞 (Trh) 如何介导 IgE 抗体的产生 以及粘膜组织的炎症。我们的初步数据显示存在 CD4+PD-1+FR4+ Trh 细胞， 暴露于过敏原的小鼠肺部的新 Tfh 样细胞亚群。我们将使用小鼠遗传方法 描述这种新细胞类型的特征并了解其在 2 型免疫中的作用。在目标 3 中，我们继续合作 与 Shiv Kale 博士一起探讨一个基本问题：为什么某些过敏原能够强烈诱导 2 型免疫。我们 将采用真菌功能基因组方法并研究真菌产生的半乳糖苷酶的作用 链格孢属。总之，这些目标的研究将确定发展背后的核心机制 以及对空气中过敏原的 2 型免疫的调节，并将提供有关以下方面的免疫学解释： 过敏性疾病的各种临床表型。最终，这些研究将表征关键的细胞途径 和参与过敏性免疫反应的分子，从而可以识别发育的关键靶标 治疗或预防哮喘和过敏性疾病的新治疗策略。 相关性（参见说明）： 患有哮喘和过敏性疾病的患者存在持续的呼吸道健康问题并且病情加重 对常见吸入性过敏原的免疫反应。该项目将调查如何接触自然 过敏原会导致、延长和加剧这些疾病。