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

• 批准号: 10580731
• 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
• 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/10580731
• 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 Cells; Epithelium; 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-10; Interleukins; Investigation; Ligands; Link; Lung; Lymphoid Cell; Modeling; Molecular; Mucous body substance; Mus; Myelogenous; Ovalbumin; Pathogenesis; Pathway interactions; Persons; 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; bronchial epithelium; burden of illness; cytokine; effective therapy; improved; in vivo; insight; interferon alpha receptor; interleukin-22; mucus hypersecretion; new therapeutic target; novel; novel therapeutic intervention; overexpression; personalized medicine; pre-clinical; protein expression; receptor; repaired; response; targeted treatment

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.

项目总结 过敏性哮喘影响全球约3亿人。随着哮喘的发病率继续上升 近年来，将免疫和病理生理机制与哮喘内型联系起来的研究具有重要意义。 建立更有针对性和更有效的治疗方法。严重的类固醇不敏感(非嗜酸性)哮喘 占当前疾病负担的一半以上，但很少有研究专注于对此进行建模 疾病子集。在严重的难治性疾病中，过敏原特异性、类固醇不敏感的T辅助细胞(Th)17和/或Th2 细胞被认为是哮喘发病的关键因素，导致肺部炎症、粘液 高分泌和呼吸道高反应性。Th17免疫细胞因子白介素22在细胞免疫中起重要作用 在维持上皮完整性和促进修复方面的作用。IL-22受体α-2(IL-22Ra2)，可溶性 IL-22受体，抑制其活性。IL-22和内源性IL-22Ra2的意义 在严重哮喘中调节它们的途径尚不清楚。除IL-22Ra2、I型干扰素外， 由干扰素α亚型和干扰素β组成，是在一定程度上改变IL-10和IL-22信号的免疫调节剂 炎症性疾病的背景。根据我们的初步和已发表的研究结果，我们假设IL- 22Ra2和I型干扰素通过阻断IL-22信号使严重过敏性呼吸道疾病(AAD)持续存在， 这是缓解AAD和维持肺上皮完整性所必需的。以下目标将 研究这一假说：1)研究IL-22Ra2是否通过改变IL-22来调节严重的AAD 肺内的生物利用度，2)确定I型干扰素是否通过诱导IL-22Ra2和限制 IL-22在肺中的活性，以及3)检测肺上皮细胞中的IL-22信号是否缓解严重的AAD 并维持肺部上皮细胞的完整性。这项申请中拟议的工作将开创研究的先河 IL-22Ra2和I型干扰素作为过敏性疾病调节因子的作用，并将发现潜在的 IL-22轴在AAD期间保护肺上皮的分子机制。这部小说是在一部 临床前动物模型和人类样本将发现治疗重症肺炎的新靶点 对标准治疗反应不佳的哮喘。