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

摘要 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， 造成严重的发病率。过去几十年哮喘的高患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 革命。哮喘的一个标志是慢性炎症和组织重塑。齐心协力已远去 描述哮喘炎症反应的特征并建立驱动的潜在机制 并长期维持下去。哮喘是一种表型表现异质性疾病，包括 几种疾病的内型或潜在的病理生理机制。与该提案相关的是一个混合的 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， 与更难治疗和类固醇耐药的哮喘有关。我们最近发现白细胞介素 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 气道炎症，与具有这种内型的哮喘患者紧密分离。我们进一步确定 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。 IL-4Rα-R576 与 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。我们 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。这些观察 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 宽容。该提案汇集了在过敏性疾病、遗传学和免疫学领域拥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 进入 TH17 细胞谱系。我们还将探索长期耐受的潜力。为了调查此事 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 并拥有良好的相互合作记录。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。

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.