The Role of IL-10 in Regulation of Allergic Inflammation

IL-10 在调节过敏性炎症中的作用

• 批准号: 6699660
• 负责人: William J Calhoun
• 金额: $ 36.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6699660
• 关键词: allergens; alveolar macrophages; apoptosis; asthma; cytokine; diagnostic respiratory lavage; disease /disorder model; eosinophil; helper T lymphocyte; histology; immunoglobulin E; inflammation; interleukin 10; laboratory mouse; leukocyte activation /transformation; neutralizing antibody; nitric oxide; respiratory function; respiratory hypersensitivity; tumor necrosis factor alpha

Persistent eosinophilic inflammation is a principal characteristic of asthma, with important physiologic consequences. The intensity of the allergic inflammatory response does not differentiate allergic subjects, with and without asthma. Inflammation in asthma, however, is prolonged. Therefore, signals that switch-off inflammation may be crucial in promoting resolution of allergic inflammation. One putative switch-off factor is the cytokine interleukin-10 [IL-10], which induces eosinophil apoptosis, and suppresses TNF-" production. We have shown that lung expression of IL-10 in allergic asthmatics is virtually absent, in contrast to allergic non- asthmatics, in whom IL-10 levels are increased compared to healthy volunteers. We propose the following Central Hypothesis: IL-10 is a critically important to the resolution of allergic inflammation. A genetically-engineered IL-10 deficient "knockout" (IL-10i) mouse strain offers the opportunity to perform critical mechanistic tests of the role of IL-10 in the allergic inflammatory process. Accordingly, the Specific Aims are to establish: 1) the pattern and timing of development and resolution of inflammation and physiologic changes following allergen sensitization and challenge, and the degree and characteristics of allergic sensitization; 2) the mechanisms which underlie the observations of Aim 1; 3) the specificity of IL-10 in mediating the anti-inflammatory response after allergen challenge, and 4) the role of TNF-" in enabling the inflammatory response to allergen challenge. These cytokines have direct and demonstrable relevance to human asthma. IL-10i mice and control strain animals will undergo allergen sensitization and challenge; allergen specific IgE, differentiation of Th1-Th2 lymphocytes, allergen-driven inflammation, and airway hyperresponsiveness will be key outcome variables. In addition, functional knock-out animals will be produced by administration of neutralizing IL-10 antibody, and will undergo similar studies. This information will provide direct evidence of the role of IL-10 in regulating allergic inflammation, and will help to ascertain the relationships between inflammation and airway hyperresponsiveness.

持续性嗜酸性粒细胞炎症是哮喘的主要特征，具有重要的生理后果。 过敏性炎症反应的强度并不能区分过敏性受试者，无论是否患有哮喘。 然而，哮喘的炎症持续时间较长。因此，关闭炎症的信号可能对于促进过敏性炎症的解决至关重要。 一种推定的关闭因子是细胞因子白细胞介素-10 [IL-10]，它诱导嗜酸性粒细胞凋亡，并抑制 TNF-α 的产生。我们已经证明，过敏性哮喘患者的肺部几乎不表达 IL-10，与此相反，过敏性非哮喘患者的 IL-10 水平比健康志愿者有所增加。我们提出以下主要建议： 假设：IL-10 对于解决过敏性炎症至关重要。 基因工程改造的 IL-10 缺陷“敲除”(IL-10i) 小鼠品系为对 IL-10 在过敏性炎症过程中的作用进行关键机制测试提供了机会。 因此，具体目标是确定： 1) 过敏原引起的炎症和生理变化的发展和消退的模式和时间 致敏和激发，以及过敏致敏的程度和特点； 2) 目标 1 观察结果的机制； 3) IL-10 在介导过敏原激发后抗炎反应中的特异性，以及 4) TNF-α 在促进对过敏原激发的炎症反应中的作用。 这些细胞因子与人类哮喘有直接且明显的相关性。 IL-10i小鼠和对照品系动物将进行过敏原致敏和激发；过敏原特异性 IgE、Th1-Th2 淋巴细胞的分化、过敏原驱动的炎症和气道高反应性将是关键的结果变量。 此外，将通过施用中和IL-10抗体来生产功能性基因敲除动物，并将进行类似的研究。 该信息将为 IL-10 在调节过敏性炎症中的作用提供直接证据，并将有助于确定炎症与气道高反应性之间的关系。