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：
10206234
负责人：
Michelle Hernandez
金额：
$ 30.17万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206234
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 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 pulmonary function recruit 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，住院率高于许多其他慢性病。急性哮喘的标准治疗皮质类固醇可抑制炎症。但是，全身类固醇的好处不是给药后几个小时有效，并且不靶向中性粒子注射病毒和过敏原引起的加重的共同特征。目前有紧急需要在急性哮喘加剧的情况下快速有效地工作的治疗气道高反应性，中性粒细胞和嗜酸性炎症的特征是和粘液分泌因清除而受损。我们假设父母的干预措施针对急性哮喘实施的炎症细胞因子可能被证明是有用的为加重的标准处理。我们对哮喘患者的研究表明暴露于污染物后的气道IL-1β反应增强。关于鼠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体，粒细胞募集，肥大细胞活化和粘液分泌；但是，确切的 IL-1β的来源尚未阐明。那就是IL-1封锁提出了小说并有针对性的处理加剧的广泛特征的策略。 Anakinra是FDA批准的IL-1接收器对抗者，动作迅速和半衰期。我们已经成功安全地使用了环境内毒素挑战后，阿纳基纳（Anakinra）减少中性粒细胞气道注入在健康的志愿者中。使用经常用于测试新颖的内部化过敏原挑战模型哮喘疗法，我们将检验中心假设，即用anakinra封锁将减少过敏性气道疾病受试者哮喘加重的三个特征：气道过度反应性，炎症，粘液分泌和清除率。 AIM 1将测试IL-1是否沸腾减轻过敏原诱导的支气管反应性。 AIM 2将测试IL-1 blocade是否减轻过敏原诱导的支气管注射。 AIM 3将测试IL-1 glocade是否减轻过敏原诱导的粘液分泌和清除减慢。我们将是第一个确定是否 Anakinra使用两种给药方案来减轻哮喘加重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精心设计的临床试验，可以测试该疗法是否是有用的辅助手段在急诊环境中使用的呼吸道疾病加剧。