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.

项目摘要过敏性哮喘影响着全球约3亿人。随着哮喘的事件继续上升，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多有针对性和有效的疗法。严重，不敏感的（非嗜酸性粒细胞）哮喘占当前疾病的一半以上，但很少有研究重点是建模疾病子集。在严重的难治性疾病中，过敏原特异性，不敏感的T助手（Th）17和/或Th2 细胞被认为批判性地编排哮喘发病机理，导致肺部炎症，粘液过度分泌和气道高反应性。 Th17免疫细胞因子白介素（IL）-22发挥重要作用在维持上皮完整性和促进维修方面的作用。 IL-22受体α-2（IL-22RA2），可溶性 IL-22的受体抑制其活性。 IL-22和内源性IL-22RA2的意义以及在严重哮喘中调节它们的途径尚不清楚。除了IL-22RA2，I型干扰素（IFN），由IFNα亚型和IFNβ组成，是在某些人中改变IL-10和IL-22信号的免疫调节剂炎症性疾病环境。根据我们的初步和发表的发现，我们假设 22RA2和I型IFN通过阻止IL-22信号传导，使严重的过敏性气道疾病（AAD）永存这是减轻AAD和维持肺上皮完整性所必需的。以下目标将研究这一假设：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是否通过诱导的IL-22RA2促进严重AAD和限制 IL-22在肺中的活性，3）检查肺上皮中的IL-22是否降低严重AAD的信号传导并保持肺中的上皮完整性。本申请中的拟议工作将开创调查进入IL-22RA2和I型干扰素作为过敏性疾病的调节剂的作用，并将发现潜力 IL-22轴在AAD期间保护肺上皮的分子机制。这本小说的作品临床前动物模型和人类样品将发现新的治疗靶标，以治疗严重对标准疗法反应不佳的哮喘。