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

基本信息

批准号：
9380678
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
项目类别：
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/9380678
关键词：
Acute Adrenal Cortex Hormones Agonist Allergens Allergic Anti-Inflammatory Agents Anti-inflammatory Asthma Basophils Blood Circulation Breathing Cells Chronic Chronic Disease Clinical Clinical Trials Design Cross-Over Studies Data Development Dose Edema Emergency Care Emergency Situation Endotoxins Exposure to Extrinsic asthma FDA approved Future Half-Life Histamine Hospitalization Hour House Dust Mite Allergens Human Human Volunteers IgE Impairment Inflammation Inflammatory 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 body substance Muscle Contraction Neutrophil Infiltration Neutrophilia Peptide Hydrolases Pharmaceutical Preparations Phase Physiology Placebo Control Placebos Production Proteins Pulmonary Function Test/Forced Expiratory Volume 1 Radionuclide Imaging Randomized Recruitment Activity 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 asthmatic chemokine clinical care cytokine disorder control early onset environmental endotoxin eosinophil eosinophilic inflammation experience falls granulocyte healthy volunteer immunoregulation improved interest macrophage mast cell methacholine monocyte mortality mouse model mucus hypersecretion neutrophil novel pollutant response standard care targeted agent volunteer

项目摘要

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，因病情恶化而住院的比率高于哮喘许多其他慢性疾病的标准治疗包括全身性哮喘。皮质类固醇可以抑制炎症，但全身性类固醇却没有这些好处。给药后数小时内有效，并且不针对中性粒细胞炎症，病毒和过敏原引起的恶化都有一个共同的特点，目前有一个紧迫的问题。需要快速有效地治疗哮喘急性发作的治疗方法，其特点是气道高反应性、中性粒细胞和嗜酸性粒细胞炎症增加，和清除受损的粘液分泌。针对与急性哮喘有关的炎症细胞因子可能被证明是有用的辅助手段我们对过敏性哮喘患者的研究表明。小鼠暴露于污染物后气道 IL-1β 反应增强。过敏性哮喘模型表明 IL-1β 是气道反应性的中心介质，然而，粒细胞募集、肥大细胞激活和粘液分泌过多； IL-1β 的来源尚未阐明，因此，IL-1 阻断提供了一种新颖且有针对性的方法。阿那白滞素 (Anakinra) 是 FDA 批准的一种 IL-1 受体。我们已成功且安全地使用了起效快、半衰期短的拮抗剂。阿那白滞素在环境内毒素挑战后减少中性粒细胞气道炎症使用常用于测试新颖的吸入过敏原挑战模型。哮喘治疗，我们将测试中心假设，即用阿那白滞素阻断 IL-1 会减少过敏性气道疾病受试者哮喘发作的三个特征：气道目标 1 将测试 IL-1 是否过度反应、炎症以及粘液分泌和清除。阻断可减轻过敏原诱导的支气管反应性，目标 2 将测试 IL-1 阻断是否有效。目标 3 将测试 IL-1 阻断是否可以减轻过敏原诱导的支气管炎症。过敏原引起的粘液分泌和清除速度减慢，我们将首先确定是否如此。阿那白滞素使用两种剂量方案缓解哮喘急性发作的这些关键特征：这些概念验证研究对于哮喘治疗方案至关重要。开发精心设计的临床试验，可以测试这种疗法是否是一种有用的辅助疗法用于紧急护理环境的呼吸系统疾病实验。