Immune Mediators of IL-22 Signaling Alter Allergic Airway Disease

IL-22 信号的免疫介质改变过敏性气道疾病

基本信息

批准号：
10112956
负责人：
Michelle Lynn Manni
金额：
$ 41.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10112956
关键词：
Affect Allergens Allergic Disease Alveolar Macrophages Animal Model Antibodies Antiinflammatory Effect Asthma Attenuated Binding Binding Proteins Biological Availability Biological Response Modifiers Bone Marrow Cells Chronic Data Dendritic Cells Development Disease Disease model Drug resistance Epithelial Epithelial Cells Extrinsic asthma Flow Cytometry Genes Goals Health Healthcare Systems Hematopoietic Human IFNAR1 gene Immune Immune response Immunomodulators Incidence Inflammation Inflammatory Injury Interferon Type I Interferon-alpha Interferons Interleukin Receptor Interleukin-10 Interleukins Investigation Ligands Link Lung Lymphoid Cell Modeling Molecular Mucous body substance Mus Myelogenous Ovalbumin Pathogenesis Pathway interactions Play Public Health Publishing Pulmonary Inflammation Pyroglyphidae Refractory Disease Reporter Role STAT1 gene STAT2 gene STAT3 gene Sampling Serum Severity of illness Signal Transduction Source Sputum Steroid Resistance Steroids Subgroup Surface Testing Th2 Cells Tissues United States Wild Type Mouse Work airway epithelium airway hyperresponsiveness allergic airway disease asthmatic asthmatic patient base bronchial epithelium burden of illness cytokine effective therapy improved in vivo insight interleukin-22 mucus hypersecretion new therapeutic target novel novel therapeutic intervention overexpression personalized medicine pre-clinical protein expression receptor repaired response targeted treatment

项目摘要

PROJECT SUMMARY Allergic asthma affects approximately 300 million people worldwide. As the incidence of asthma continues to rise, studies linking immune and pathophysiologic mechanisms to asthma endotypes are of great importance to establish more targeted and effective therapies. Severe, steroid-insensitive (non-eosinophilic) asthma accounts for greater than half the current disease burden, but few studies have focused on modeling this disease subset. In severe refractory disease, allergen-specific, steroid-insensitive T helper (Th) 17 and/or Th2 cells are thought to critically orchestrate asthma pathogenesis, resulting in pulmonary inflammation, mucus hypersecretion, and airway hyperresponsiveness. The Th17 immune cytokine interleukin (IL)-22 plays a vital role in maintaining epithelial integrity and promoting repair. IL-22 receptor alpha-2 (IL-22Ra2), a soluble receptor for IL-22, inhibits its activity. The significance of IL-22 and endogenous IL-22Ra2, as well as the pathways that regulate them in severe asthma, are unknown. Aside from IL-22Ra2, type I interferons (IFN), consisting of IFNα subtypes and IFNβ, are immunomodulators that alter IL-10 and IL-22 signaling in certain inflammatory disease contexts. Based on our preliminary and published findings, we hypothesize that IL- 22Ra2 and type I IFNs perpetuate severe allergic airway disease (AAD) by blocking IL-22 signaling, which is necessary to alleviate AAD and maintain epithelial integrity in the lung. The following aims will investigate this hypothesis: 1) Investigate whether IL-22Ra2 modulates severe AAD by altering IL-22 bioavailability in the lung, 2) Determine if type I IFNs promote severe AAD by inducing IL-22Ra2 and limiting IL-22 activity in the lung, and 3) Examine if IL-22 signaling in the epithelium of the lung alleviates severe AAD and maintains epithelial integrity in the lung. The proposed work in this application will pioneer investigations into the role of IL-22Ra2 and type I interferons as regulators of allergic disease and will uncover the potential molecular mechanisms by which the IL-22 axis protects the lung epithelium during AAD. This novel work in a preclinical animal model and human samples will uncover new therapeutic targets for the treatment of severe asthma that is poorly responsive to standard therapies.

项目概要随着哮喘发病率持续上升，过敏性哮喘影响着全球约 3 亿人。上升，将免疫和病理生理机制与哮喘内型联系起来的研究非常重要建立更有针对性和更有效的治疗方法。占当前疾病负担的一半以上，但很少有研究关注这一点的建模在严重难治性疾病中，过敏原特异性、类固醇不敏感 T 辅助细胞 (Th) 17 和/或 Th2 人们认为细胞对哮喘发病机制有重要作用，导致肺部炎症、粘液 Th17 免疫细胞因子白细胞介素 (IL)-22 起着至关重要的作用。维持上皮完整性和促进修复的作用 IL-22 受体 α-2 (IL-22Ra2)，一种可溶性的。 IL-22 受体，抑制其活性 IL-22 和内源性 IL-22Ra2 的意义以及除了 IL-22Ra2、I 型干扰素 (IFN) 之外，在严重哮喘中调节它们的途径尚不清楚。由 IFNα 亚型和 IFNβ 组成，是在某些情况下改变 IL-10 和 IL-22 信号传导的免疫调节剂根据我们的初步和已发表的研究结果，我们研究了 IL- 22Ra2 和 I 型干扰素通过阻断 IL-22 信号传导使严重过敏性气道疾病 (AAD) 长期存在，这是缓解 AAD 和维持肺上皮完整性所必需的。研究这一假设：1) 研究 IL-22Ra2 是否通过改变 IL-22 来调节严重的 AAD 肺中的生物利用度，2) 确定 I 型 IFN 是否通过诱导 IL-22Ra2 和限制来促进严重的 AAD 肺部的 IL-22 活性，以及 3) 检查肺部上皮细胞中的 IL-22 信号传导是否可以缓解严重的 AAD 并维持肺部上皮的完整性。本申请中提出的工作将开创性的研究。深入研究 IL-22Ra2 和 I 型干扰素作为过敏性疾病调节剂的作用，并将揭示其潜力 IL-22 轴在 AAD 期间保护肺上皮的分子机制。临床前动物模型和人体样本将揭示治疗重症的新治疗靶点对标准疗法反应不佳的哮喘。