IL-1 receptor blockade as a novel treatment for exacerbation of allergic airway responses in humans

IL-1受体阻断作为人类过敏性气道反应恶化的新型治疗方法

• 批准号: 10013283
• 负责人: Michelle Hernandez
• 金额: $ 60.35万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013283
• 关键词: Acute; Adrenal Cortex Hormones; Agonist; Allergens; Allergic; Anti-Inflammatory Agents; Asthma; Basophils; Blood Circulation; Cells; Chronic; Chronic Disease; Clinical; Clinical Trials Design; Cross-Over Studies; Data; Development; Dose; Edema; Emergency Care; Endotoxins; Eosinophil cationic protein; Exposure to; Extrinsic asthma; FDA approved; Future; Half-Life; Histamine; Hour; House Dust Mite Allergens; Human; Human Volunteers; IgE; Immunomodulators; Impairment; Inflammation; Inflammatory; Inhalation; Innate Immune Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-5; Intervention; Literature; Lung diseases; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Muscle Contraction; Neutrophil Infiltration; Neutrophilia; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Physiology; Placebos; Production; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Radionuclide Imaging; Randomized; Regimen; Reporting; Resistance; Respiratory physiology; Role; Sampling; Scheme; Secretory Vesicles; Severities; Signal Transduction; Smooth Muscle; Source; Sputum; Steroids; Symptoms; Testing; Viral; Work; airway hyperresponsiveness; airway inflammation; airway obstruction; allergic airway disease; allergic airway inflammation; anakinra; asthma exacerbation; asthma model; asthmatic; chemokine; clinical care; cytokine; disorder control; early onset; emergency settings; environmental endotoxin; eosinophil; eosinophilic inflammation; experience; falls; granulocyte; healthy volunteer; hospitalization rates; improved; interest; macrophage; mast cell; methacholine; monocyte; mortality; mouse model; mucus hypersecretion; neutrophil; novel; pollutant; primary endpoint; recruit; response; standard care; targeted agent; volunteer

Asthma is a common chronic illness with higher rates of hospitalization for exacerbation than many other chronic conditions. Standard treatment for acute asthma includes systemic corticosteroids to suppress inflammation. However, the benefits of systemic steroids are not effective for several hours after administration and do not target neutrophilic inflammation, a shared feature of both viral- and allergen-induced exacerbations. Currently there is an urgent need for treatments that work quickly and effectively in acute asthma exacerbations, characterized by increased airway hyper-reactivity, neutrophilic and eosinophilic inflammation, and mucous secretion with impaired clearance. We hypothesize that parenteral interventions targeted at inflammatory cytokines implicated in acute asthma may prove to be useful adjuncts to standard treatment of exacerbations. Our studies with allergic asthmatics have shown enhanced airway IL-1β responses after exposure to pollutants. Numerous studies in murine models of allergic asthma indicate that IL-1β is a central mediator of airway reactivity, granulocyte recruitment, mast cell activation, and mucus hypersecretion; however, the exact source of IL-1β has yet to be elucidated. Thus, IL-1 blockade presents a novel and targeted strategy to treat broad features of an exacerbation. Anakinra is a FDA-approved IL-1 receptor antagonist with a fast onset of action and short half-life. We have successfully and safely used anakinra in reducing neutrophilic airway inflammation after environmental endotoxin challenge in healthy volunteers. Using a model of inhaled allergen challenge frequently used to test novel asthma therapies, we will test the central hypothesis that IL-1 blockade with anakinra will reduce three features of asthma exacerbations in subjects with allergic airway disease: airway hyperreactivity, inflammation, and mucous secretion and clearance. Aim 1 will test if IL-1 blockade mitigates allergen-induced bronchial reactivity. Aim 2 will test if IL-1 blockade mitigates allergen-induced bronchial inflammation. Aim 3 will test if IL-1 blockade mitigates allergen-induced mucus secretion and slowed clearance. We will be the first to determine if anakinra alleviates these key features of asthma exacerbations using two dosing schemes that reflect potential asthma rescue regimens. These proof-of-concept studies are essential to the development of well-designed clinical trials that can test if this therapy is a useful adjunct in exacerbations of respiratory disease for use in emergency care settings.

哮喘是一种常见的慢性疾病， 许多其他慢性疾病。急性哮喘的标准治疗包括全身性 皮质类固醇来抑制炎症然而，全身性类固醇的益处并不 给药后数小时有效，不针对嗜中性炎症， 病毒和过敏原诱导的急性加重的共同特征。目前，有一个紧急 需要快速有效地治疗急性哮喘恶化， 其特征在于气道高反应性增加，嗜酸性和嗜酸性炎症， 以及清除率受损的粘液分泌。我们假设肠外干预 针对急性哮喘中涉及的炎性细胞因子， 急性加重的标准治疗我们对过敏性哮喘患者的研究表明 暴露于污染物后增强气道IL-1β反应。在小鼠中进行的大量研究 过敏性哮喘模型表明IL-1β是气道反应性的中心介质， 粒细胞募集、肥大细胞活化和粘液分泌过多;然而， IL-1β的来源尚未阐明。因此，IL-1阻断呈现了一种新的靶向的 治疗急性加重的广泛特征的策略。阿那白滞素是FDA批准的IL-1受体 拮抗剂起效快，半衰期短。我们已经成功安全地使用了 阿那白滞素减轻环境内毒素刺激后的嗜酸性气道炎症 健康志愿者。使用经常用于测试新的吸入性过敏原攻击模型， 哮喘治疗，我们将测试中心假设，白细胞介素-1阻滞与阿那白滞素将减少 过敏性气道疾病患者哮喘急性发作的三个特征：气道 高反应性、炎症和粘液分泌和清除。目标1将测试IL-1是否 阻断减轻了过敏原诱导的支气管反应性。目标2将测试IL-1阻断是否 减轻过敏原诱导的支气管炎症。目标3将测试IL-1阻断是否减轻 过敏原诱导的粘液分泌和清除减慢。我们将第一个确定 阿那白滞素使用两种给药方案来描述哮喘急性发作的这些关键特征， 反映了潜在的哮喘补救方案。这些概念验证研究对于 开发设计良好的临床试验，可以测试这种疗法是否是一种有用的辅助治疗， 呼吸道疾病恶化，用于紧急护理环境。