Airway Dendritic Cells in the Allergic Asthma Phenotype

过敏性哮喘表型中的气道树突状细胞

• 批准号: 9917696
• 负责人: Josalyn L Cho
• 金额: $ 23.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-18 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917696
• 关键词: Affect; Allergens; Allergic; Animal Model; Antigen-Presenting Cells; Asthma; B-Cell Activation; B-Lymphocytes; Biological Response Modifier Therapy; Biopsy; Bronchoalveolar Lavage; Bronchus-Associated Lymphoid Tissue; Cell Communication; Cells; Data; Dendritic Cells; Development; Disease; Disease remission; Epithelial; Epithelium; Exposure to; Extrinsic asthma; Genetic Transcription; Goals; Human; Hypersensitivity; IgE; Immune; Immune response; Immunoglobulins; Immunologic Memory; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inhalation; Investigation; Lead; Lung; Lymphocyte; Lymphoid; Lymphoid Tissue; Measures; Mediator of activation protein; Memory; Mucositis; Mucous Membrane; Pathogenesis; Pathogenicity; Patients; Phenotype; Plasma Cells; Play; Prevalence; Production; Publishing; Regulation; Research; Risk Factors; Role; Sampling; Severities; Signal Transduction; Site; Structure; Symptoms; T cell response; T memory cell; T-Cell Proliferation; T-Lymphocyte; Th2 Cells; Time; Tissues; airway inflammation; asthma exacerbation; asthmatic; asthmatic airway; base; cytokine; effector T cell; experience; experimental study; in vivo; in vivo Model; insight; mouse model; mucosal site; new therapeutic target; novel therapeutics; programs; receptor; recruit; response; single-cell RNA sequencing; targeted treatment; tumor-immune system interactions

Project Summary Asthma affects more than 300 million individuals worldwide, and more than half of patients with asthma have inadequately controlled symptoms and frequent exacerbations. Advances in our understanding of the immunology of asthma have led to the development of targeted biologic therapies against a single cytokine or receptor. Although these targeted therapies reduce exacerbations, they have not demonstrated disease modifying effects. Most asthma is allergic in origin, and the strongest risk factor for allergic asthma is allergy. Not all allergic patients have asthma, but many develop the disease over time, suggesting there are incremental and potentially reversible stages in the development of allergic asthma. Thus, identification of differences between allergic asthmatics (AA) and allergic non-asthmatic controls (AC) may provide insight into the mechanisms that ultimately lead to the development of asthma. The long-term goal of this research is to determine how dendritic cells (DC) orchestrate secondary immune responses in the lung and ultimately identify novel therapeutic targets aimed at inducing asthma remission. DC are critical regulators of the effector T cell response in the lung mucosa, and our previously published data suggest there are key differences in re-activation of allergen-specific T helper type 2 (Th2) cells during secondary responses in the lung. Therefore, we hypothesize that differences in airway DC between AA and AC determine the asthma phenotype. For this proposal, we will utilize bronchoscopic segmental allergen challenge (SAC) to mimic an asthma exacerbation in AA and AC and compare the immune response in the airway. Our preliminary data suggests that a subset of conventional DC in the bronchoalveolar lavage (BAL) may be more activated at baseline in AA compared to AC and that AA have higher levels of Th2- type cytokines and IgE in the airways following SAC. Furthermore, DC in AA may accumulate in the airway mucosa after allergen challenge. Finally, we demonstrate that the airway mucosa may be a separate immune microenvironment and identify the cellular components of inducible bronchus associated lymphoid tissue (iBALT) in mucosal samples. Based on these data we propose: Aim #1 to compare the phenotype of airway mucosal DC and BAL DC in AA and AC and Aim #2 to determine the transcriptional identity of airway mucosal immune cells in AA and AC. In Aim #1, we will compare the phenotype of DC isolated from BAL and the airway mucosa (using endobronchial brushing) of AA and AC at baseline and after SAC. We will also assess for known mediators of iBALT formation. In Aim #2, we will perform a comprehensive, unbiased transcriptional analysis of the immune cells in the airway mucosa using single-cell RNA sequencing (scRNAseq). We will also obtain endobronchial biopsies to assess for the presence of organized iBALT and validate the findings from scRNAseq. We believe these studies will advance our understanding of asthma pathogenesis by defining the relevant human lung DC subsets and providing insight into the airway microenvironment. Our results will form the basis of more targeted investigations using animal models, in vitro experiments and further translational human studies.

项目摘要 全世界有超过3亿人患有哮喘，超过一半的哮喘患者患有 症状控制不充分，病情经常恶化。我们对这一现象的理解取得了进展 哮喘的免疫学导致了针对单一细胞因子或 受体。尽管这些靶向治疗减少了病情恶化，但它们并没有显示出疾病的存在。 修改效果。大多数哮喘都是过敏性的，过敏性哮喘的最大危险因素是过敏。不 所有过敏性患者都有哮喘，但随着时间的推移，许多人会发展成这种疾病，这表明有增量和 变态反应性哮喘发展过程中的潜在可逆阶段。因此，识别两者之间的差异 过敏性哮喘患者(AA)和过敏性非哮喘对照(AC)可提供对 最终导致哮喘的发展。这项研究的长期目标是确定树突如何 细胞(DC)在肺中协调二次免疫反应，并最终识别新的治疗靶点 旨在诱导哮喘缓解。DC是肺粘膜效应性T细胞反应的关键调节因子， 我们之前发表的数据表明，在过敏原特异性T辅助细胞的重新激活方面存在关键差异 肺内二次反应中的2型(Th2)细胞。因此，我们假设呼吸道的差异 AA和AC之间的DC决定了哮喘的表型。对于这项提议，我们将使用支气管镜 节段性变应原激发(SAC)在AA和AC中模拟哮喘加重并比较免疫 呼吸道的反应。我们的初步数据表明，支气管肺泡中的一部分常规DC 与AC组相比，AA组的灌洗液(BAL)在基线时可能更活跃，而且AA组的Th2- SAC后呼吸道细胞因子和IgE分型。此外，再生障碍性贫血中的DC可能会在呼吸道中积聚。 变应原激发后的粘膜。最后，我们证明了呼吸道粘膜可能是一种独立的免疫。 诱导的支气管相关淋巴组织的微环境和细胞成分的鉴定 在粘膜样本中。基于这些数据，我们提出：目的1比较呼吸道粘膜的表型 AA和AC中的DC和BAL DC以及Aim#2确定呼吸道粘膜免疫的转录同一性 AA和AC中的细胞。在目标1中，我们将比较从BAL和呼吸道粘膜分离的DC的表型。 (使用支气管镜刷牙)在基线和SAC后测定AA和AC。我们还将评估已知调解人 IBALT队形。在目标2中，我们将对免疫进行全面、公正的转录分析。 用单细胞RNA测序(ScRNAseq)检测呼吸道粘膜中的细胞。我们还将获得支气管内膜 活检以评估是否存在有组织的iBALT，并验证scRNAseq的发现。我们相信 这些研究将通过定义相关的人类肺树突状细胞来促进我们对哮喘发病机制的理解 并提供对呼吸道微环境的洞察。我们的结果将形成更有针对性的基础 使用动物模型、体外实验和进一步的转译人体研究进行研究。