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比例， 导致了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： 受影响的个体的易感基因与环境和生活方式的变化带来的工业 革命哮喘的一个标志是慢性炎症和组织重塑。协调一致的努力已经消失了 描述哮喘炎症反应的特征，并建立驱动哮喘的潜在机制， 并长期维持。哮喘是一种表型表现不均一的疾病， 几种疾病内型，或潜在的病理生理机制。与这项建议有关的是一个混合的 TH 2/TH 17内型，其特征在于气道中的混合嗜酸性和嗜酸性炎症， 与更难治疗和类固醇抵抗性哮喘有关。我们最近发现， 与严重哮喘相关的IL-4受体（IL-4 R）变体，IL-4 R α-R576，独特地驱动混合TH 2/TH 17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 这种变体促进混合性TH 2/TH 17炎症的机制涉及IL-4依赖性 将过敏原特异性诱导的调节性T（iTreg）细胞颠覆为TH 17细胞样表型，导致其 退化成真正的过敏原特异性致病性TH 17细胞。IL-4 R α-R576与 严重且难以治疗的哮喘，并且在市中心的儿科年龄哮喘患者中特别常见。我们 在比较野生型（Q576/Q576）、杂合型（Q576/Q576）、 突变（Q576/R576）和纯合（R576/R576）突变等位基因与哮喘发病率的关系。这些观察结果 提供使用抗IL-4 R单克隆抗体（mAb）Dupilumab阻断IL-4 R的依据， 阻断IL-4依赖性混合TH 2/TH 17细胞炎症并同时恢复 宽容这项提案汇集了在过敏性疾病，遗传学和 耐受性，以解决这一假设，即儿童年龄哮喘窝藏这种变异将表现出一种 对Dupilumab的反应特别有利，IL-4 R α-R576变体驱动混合TH 2/TH 17细胞 通过破坏过敏原特异性诱导的T调节（iTreg）细胞应答， TH 17细胞系。我们还将探索长期耐受性的潜力。调查这一 总体假设本试验和机制研究由公认的专业知识研究者领导 并有良好的合作记录。我们将检查这些药物的临床反应， 根据基因型对儿童进行治疗，并检查T细胞炎症和调节的演变 根据接受安慰剂或Dupilumab治疗的哮喘儿童的IL-4 R基因型分层的缓解。 这些研究有望通过IL-4 R α-R576指导精确的医学指导的有效治疗。 基因型，特别是针对疾病驱动型内型的儿童难以治疗的哮喘。

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.