Local B cell memory in airway hypersensitivity.

气道超敏反应中的局部 B 细胞记忆。

• 批准号: 10684304
• 负责人: Alexander James Nelson
• 金额: $ 2.89万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684304
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Airway Disease; Allergens; Anatomy; Antibody Formation; Antibody Response; Antibody-Producing Cells; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Biology; Cell Separation; Cells; Characteristics; Circulation; Cues; Development; Disease; Environment; Exhibits; Exposure to; Extrinsic asthma; Fellowship; Generations; Goals; Host Defense; Human; Hypersensitivity; IgE; Imaging technology; Immune; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Intercept; Knowledge; Life; Local Therapy; Location; Lung; Maintenance; Memory B-Lymphocyte; Microscopy; Molecular; Mus; Parabiosis; Pathogenicity; Patients; Population; Prevalence; Prevention; Production; Research Personnel; Residencies; Resolution; Respiratory Mucosa; Respiratory System; Respiratory Tract Infections; Respiratory distress; Role; Source; Specificity; Structure of parenchyma of lung; Systemic disease; Therapeutic Intervention; Tissues; adaptive immune response; airway hyperresponsiveness; airway inflammation; allergic airway disease; allergic response; asthmatic; asthmatic patient; career; cell type; chronic inflammatory disease; constriction; effective therapy; experimental study; in vivo; influenzavirus; mouse model; neutralizing antibody; new therapeutic target; prevent; pulmonary function; recruit; respiratory pathogen; response; source localization; therapeutically effective; trafficking; transcriptomics

Project Summary/Abstract Allergic asthma is a chronic inflammatory disease of the airway that currently has no cure. Production of immunoglobulin E (IgE) to inhaled allergens drives inflammation and the allergic response seen in allergic asthma. Over half of patients exhibit allergen-specific IgE at the respiratory mucosa but not systemically in circulation, illustrating the importance of local production of IgE. However, the mechanisms that promote and maintain local pathogenic IgE responses are not understood. Using a mouse model of airway hypersensitivity, we have identified a population of memory B cells that localize to the lungs after repeated exposures to inhaled allergens. These lung-localized memory B cells exhibit specificity for allergens, persist after the resolution of inflammation, expand upon re-challenge with increase of local allergen-specific IgE. We hypothesize that tissue- resident memory B cells are the major source of local responses in asthmatic lungs, responsible for maintaining long-term hypersensitivity in the airway. In this proposal, we will elucidate the cellular environment that maintains lung residency of memory B cells in asthmatic lungs and investigate their functions in airway hypersensitivity. Specifically, in Aim 1, using in vivo depletion of circulating cells and parabiosis experiments we will verify the tissue-residency of memory B cells in asthmatic lungs. We will identify the potential niches of lung-localized memory B cells and examine the cellular environment responsible for their maintenance in the lungs using cutting-edge imaging technologies. In Aim 2, we will inhibit recruitment of circulating B cells during re-challenge and perform adoptive cell transfer of tissue-resident memory B cells to delineate the function of tissue-resident memory B cells in airway hypersensitivity. In summary, we aim to shed light on the fundamental biology of memory B cells in the respiratory tract and reveal their functions in airway hypersensitivity. This study may reveal a crucial cell population that can be targeted to treat or prevent the progression of allergic asthma in humans. This fellowship will provide the crucial support for the applicant to pursue a career as an independent investigator in immunology.

项目概要/摘要 过敏性哮喘是一种慢性气道炎症性疾病，目前尚无治愈方法。生产 吸入过敏原的免疫球蛋白 E (IgE) 会导致炎症和过敏反应 哮喘。超过一半的患者在呼吸道粘膜处表现出过敏原特异性 IgE，但在全身情况下并未表现出过敏原特异性 IgE。 循环，说明了 IgE 本地生产的重要性。然而，促进和 维持局部致病性 IgE 反应尚不清楚。使用气道过敏的小鼠模型， 我们已经鉴定出一群记忆 B 细胞，在反复吸入空气后定位于肺部。 过敏原。这些肺部定位的记忆 B 细胞对过敏原表现出特异性，在过敏原消退后仍持续存在。 随着局部过敏原特异性 IgE 的增加，再次攻击时炎症会扩大。我们假设组织- 常驻记忆 B 细胞是哮喘肺部局部反应的主要来源，负责维持 气道长期过敏。在本提案中，我们将阐明维持 记忆 B 细胞在哮喘肺部的肺部驻留并研究它们在气道过敏中的功能。 具体来说，在目标 1 中，我们将利用体内循环细胞耗竭和联体共生实验来验证 记忆 B 细胞在哮喘肺部的组织驻留。我们将确定肺部局部的潜在利基 记忆 B 细胞并使用以下方法检查负责维持其在肺部的细胞环境 尖端成像技术。在目标 2 中，我们将在重新攻击期间抑制循环 B 细胞的募集 并对组织驻留记忆 B 细胞进行过继细胞转移，以描绘组织驻留记忆 B 细胞的功能 气道超敏反应中的记忆 B 细胞。总之，我们的目标是阐明基础生物学 呼吸道中的记忆 B 细胞并揭示其在气道过敏中的功能。这项研究可能会揭示 一个关键的细胞群，可用于治疗或预防人类过敏性哮喘的进展。 该奖学金将为申请人追求独立调查员的职业生涯提供至关重要的支持 在免疫学中。