Effect of IL-4RαR576 variant on response to Dupilumab in children with Asthma

IL-4RαR576 变异对哮喘儿童 Dupilumab 反应的影响

基本信息

批准号：
9912720
负责人：
Talal Amine Chatila
金额：
$ 243.22万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-11 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912720
关键词：
Accident and Emergency department Address Adoption Adrenal Cortex Hormones Affect Age Agonist Alleles Allergens Allergic Disease Applications Grants Asthma Automobile Driving Bronchodilator Agents Cell Lineage Cells Child Childhood Chronic Clinical Collaborations Coughing Development Disease Dose Double-Blind Method Epidemic Evolution Gene Expression Profiling Genetic Genotype Health High Prevalence Hospitalization Human Individual Industrialization Inflammation Inflammatory Inflammatory Response Interleukin 4 Receptor Interleukin-13 Interleukin-17 Interleukin-4 Interruption Investigation Life Style Mediating Medical Monoclonal Antibodies Morbidity - disease rate Outcome Pathogenicity Patients Phase Phase II Clinical Trials Phenotype Placebos Prevalence Pulmonary Function Test/Forced Expiratory Volume 1 Randomized Research Personnel Signal Transduction Steroid-resistant asthma Susceptibility Gene T-Lymphocyte Testing Tissues Variant Visit Wheezing asthma exacerbation asthmatic base effective therapy eosinophil epigenetic profiling experience immunoregulation improved inner city mutant neutrophil personalized medicine precision medicine primary outcome randomized placebo controlled trial receptor response restoration secondary outcome targeted treatment

项目摘要

Abstract Asthma is a major health problem worldwide whose prevalence has reached epidemic proportions and that exacts a heavy toll of morbidity. The high prevalence of asthma over the last decades reflects the interaction of susceptibility genes in affected individuals with environmental and life style changes ushered by the industrial revolution. A hallmark of asthma is chronic inflammation and tissue remodeling. Concerted efforts have gone into characterizing the asthmatic inflammatory response and establishing the underlying mechanisms that drive and sustain it long-term. Asthma, a heterogeneous disorder in its phenotypic manifestations, encompasses several disease endotypes, or underlying pathophysiologic mechanisms. Relevant to this proposal is a mixed TH2/TH17 endotype characterized by mixed eosinophilic and neutrophilic inflammation in the airways and is associated with more difficult to treat and steroid-resistant asthma. We have recently shown that an interleukin 4 receptor (IL-4R) variant associated with severe asthma, IL-4Rα-R576, uniquely drives mixed TH2/TH17 cell inflammation in the airways, tightly segregating with asthmatics with this endotype. We have further determined that the mechanism by which this variant promotes mixed TH2/TH17 inflammation involves IL-4-dependent subversion of allergen-specific induced regulatory T (iTreg) cells into a TH17 cell-like phenotype, leading to their degeneration into bona fide allergen-specific pathogenic TH17 cells. The IL-4Rα-R576 is associated with severe and difficult to treat asthma, and is particularly common among inner city pediatric age asthmatics. We established dose response relationships with IL-17 in comparing the wild type (Q576/Q576), heterozygous mutant (Q576/R576), and homozygous (R576/R576) mutant alleles and asthma morbidity. These observations provide the rationale to use IL-4R blockade with the anti-IL-4R monoclonal antibody (mAb) Dupilumab with the dual purpose of interrupting the IL-4-dependent mixed TH2/TH17 cell inflammation and simultaneously restoring tolerance. This proposal brings together investigators with deep expertise in allergic diseases, genetics and tolerance to address the hypothesis that pediatric age asthmatics harboring this variant will manifest a particular favorable response to Dupilumab and that the IL-4Rα-R576 variant drives mixed TH2/TH17 cell inflammation in the airways by subverting allergen-specific induced T regulatory (iTreg) cell responses into the TH17 cell lineage. We will also explore the potential of long-term tolerance. To investigate this overarching hypothesis this trial and mechanistic studies are led by investigators recognized for their expertise and with a proven track record of collaboration with each other. We will examine the clinical response of these children to therapy based on genotype and examine the evolution of the T cell inflammatory and regulatory responses in asthmatic children stratified by their IL-4R genotype treated with either placebo or Dupilumab. These investigations promise precision medicine-guided effective therapy directed by the IL-4Rα-R576 genotype that specifically targets a disease-driving endotype in children with difficult to treat asthma.

抽象的哮喘是世界范围内的一个主要健康问题，其患病率已达到流行病的程度，过去几十年哮喘的高发病率反映了以下因素的相互作用。工业化带来的环境和生活方式变化影响个体的易感基因哮喘的一个标志是慢性炎症和组织重塑。描述哮喘炎症反应的特征并建立驱动的潜在机制并长期维持哮喘，其表型表现是一种异质性疾病。与该提议相关的几种疾病内型或潜在的病理生理机制是混合的。 TH2/TH17 内型以气道中嗜酸性粒细胞和中性粒细胞混合性炎症为特征，我们最近发现，白细胞介素与更难治疗和类固醇耐药的哮喘有关。与严重哮喘相关的 4 受体 (IL-4R) 变体 IL-4Rα-R576 独特地驱动混合 TH2/TH17 细胞我们进一步确定了气道炎症，与具有这种内型的哮喘患者紧密分离。该变体促进 TH2/TH17 混合炎症的机制涉及 IL-4 依赖性过敏原特异性诱导调节性 T (iTreg) 细胞颠覆为 TH17 细胞样表型，导致其退化为真正的过敏原特异性致病性 TH17 细胞与 IL-4Rα-R576 相关。严重且难以治疗的哮喘，在市中心儿童哮喘患者中尤为常见。在比较野生型 (Q576/Q576)、杂合子时建立了与 IL-17 的剂量反应关系突变体（Q576/R576）和纯合子（R576/R576）突变等位基因与哮喘发病率的关系。提供使用 IL-4R 阻断剂与抗 IL-4R 单克隆抗体 (mAb) Dupilumab 和中断 IL-4 依赖性混合 TH2/TH17 细胞炎症并同时恢复的双重目的该提案汇集了在过敏性疾病、遗传学和耐受性方面具有深厚专业知识的研究人员。耐受性来解决以下假设：携带这种变异的儿童哮喘患者将表现出对 Dupilumab 特别有利的反应以及 IL-4Rα-R576 变体驱动混合 TH2/TH17 细胞通过破坏过敏原特异性诱导的 T 调节 (iTreg) 细胞反应来抑制气道炎症我们还将探索长期耐受性的潜力。总体假设该试验和机制研究由因其专业知识而受到认可的研究人员领导并通过相互合作的良好记录，我们将检查这些药物的临床反应。儿童接受基于基因型的治疗并检查 T 细胞炎症和调节的演变根据接受安慰剂或 Dupilumab 治疗的 IL-4R 基因型对哮喘儿童的反应进行分层。这些研究有望实现由 IL-4Rα-R576 指导的精准医学指导的有效治疗专门针对难以治疗的哮喘儿童的疾病驱动内型的基因型。