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型免疫力和过敏性疾病的发展。夸张的2型免疫反应与 从哮喘到食物过敏的各种疾病。传统上，CD4+ 2型辅助者t（Th2）细胞 生产白介素（IL）-4，IL-5和IL-13被认为是指导该公司的主要参与者 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。在上一个 该优点奖的资金期限，我们在所有三个目标中都取得了重大进展。我们发现过敏原 - 特定的T卵泡辅助器（TFH）细胞和组织居民记忆（TRM）细胞在过敏免疫中起着不同的作用 回答。具体而言，TFH细胞促进了过敏原特异性IgE抗体的产生和开发 急性过敏反应，而Th2型TRM细胞可能在过敏原诱导2型细胞因子的产生和 粘膜组织中的嗜酸性炎症。在这里，我们要求将优点奖延长为5年 继续研究2型免疫力的免疫机制。我们将最终确定并至少提交4 进度报告中描述的手稿。我们将延长上一个资金期的研究 并定义过敏原暴露如何介导过敏性疾病的各种免疫和临床表型。在 AIM 1，我们将检查Th2型TRM细胞在介导2型细胞因子产生和 气道粘膜中的嗜酸性炎症。我们将利用鼠标模型并使用抛物线和 批判性定义TRM细胞功能及其调节的免疫学和遗传学方法 机制。在AIM 2中，我们将研究肺T常驻助手（TRH）细胞如何介导IgE抗体的产生 和粘膜组织中的炎症。我们的初步数据显示CD4+PD-1+FR4+TRH细胞的存在，A 暴露于过敏原的小鼠肺中TFH样细胞的新子集。我们将使用鼠标遗传方法 表征这种新的细胞类型，并了解其在2型免疫中的作用。在AIM 3中，我们继续合作 与Shiv Kale博士一起，问一个基本问题，为什么某些过敏原牢固地诱导2型免疫力。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 替代。这些目标的研究将共同​​定义开发的基础机制 和对机载过敏原的2型免疫的调节，并将提供有关免疫学解释 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（S） 和参与过敏免疫反应的分子，从 治疗或预防哮喘和过敏性疾病的新型治疗策略。 相关性（请参阅说明）： 哮喘和过敏性疾病的患者患有持续的呼吸健康问题，并夸大了 对常见吸入过敏原的免疫反应。该项目将调查如何接触自然 过敏原引起，延长和加强这些疾病。