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

哮喘是一种常见的慢性病，其急性加重的住院率高于 许多其他慢性疾病。急性哮喘的标准治疗包括全身性治疗 用来抑制炎症的皮质类固醇。然而，全身类固醇的好处并不是 在给药后几个小时有效，不针对中性粒细胞炎症， 病毒和过敏原引起的恶化的共同特征。目前有一项紧急情况 需要对急性哮喘恶化迅速有效的治疗方法， 以呼吸道高反应性、中性粒细胞和嗜酸性炎症增加为特征， 粘液分泌，清除功能受损。我们假设肠外干预 针对急性哮喘中涉及的炎性细胞因子可能被证明是有用的辅助因素 对病情恶化的标准治疗。我们对过敏性哮喘患者的研究表明 暴露于污染物后，呼吸道IL-1β反应增强。对小鼠的大量研究 过敏性哮喘模型表明，IL-1β是呼吸道反应性的中枢介质， 粒细胞募集、肥大细胞激活和粘液高分泌；然而，确切的 IL-1β的来源尚不清楚。因此，IL-1的阻断呈现出一种新颖的、有针对性的 治疗病情恶化的广泛特征的策略。Anakinra是FDA批准的IL-1受体 起效快、半衰期短的拮抗剂。我们已经成功和安全地使用了 阿纳金纳减轻环境内毒素攻击后中性粒细胞气道炎症 在健康的志愿者中。使用一种经常用于测试新奇事物的吸入性过敏原挑战模型 哮喘的治疗，我们将测试核心假设，即用阿纳金纳阻断IL-1将减少 过敏性呼吸道疾病患者哮喘加重的三个特征：呼吸道 高反应性、炎症、粘液分泌和清除。AIM 1将测试IL-1是否 阻断可减轻过敏原诱导的支气管反应性。AIM 2将测试IL-1是否被阻断 减轻过敏原引起的支气管炎。AIM 3将测试IL-1阻断是否缓解 过敏原诱导粘液分泌，清除减慢。我们将第一个确定 Anakinra使用两种剂量方案缓解哮喘恶化的这些关键特征 反映潜在的哮喘救援方案。这些概念验证研究对于 开发设计良好的临床试验，以测试这种疗法是否是一种有用的辅助疗法 呼吸系统疾病的恶化，用于紧急护理环境。

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.