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

• 批准号: 10592379
• 负责人: Talal Amine Chatila
• 金额: $ 145.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592379
• 关键词: Accident and Emergency department; Address; Adoption; Adrenal Cortex Hormones; Adult; 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; Heterozygote; High Prevalence; Hospitalization; Human; IL17 gene; Individual; Industrialization; Inflammation; Inflammatory; Inflammatory Response; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Interruption; Investigation; Life Style; Mediating; Medical; Monoclonal Antibodies; Morbidity - disease rate; Outcome; Pathogenicity; Patients; Phase; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Prevalence; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Regulatory T-Lymphocyte; Research Personnel; Signal Transduction; Steroid-resistant asthma; Susceptibility Gene; T-Lymphocyte; Testing; Tissues; Variant; Visit; Wheezing; asthma exacerbation; asthmatic; 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; segregation; targeted treatment

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 哮喘是全球一个主要的健康问题，其患病率已达到流行病，并且 严重的发病率造成了沉重的损失。在过去的几十年中，哮喘的高患病率反映了 具有环境和生活方式的受影响个体的易感基因因工业而变化 革命。哮喘的标志是慢性注射和组织重塑。一致的努力消失了 表征哮喘发炎反应并建立驱动的基本机制 并长期维持它。哮喘，其表型表现中的一种异质性疾病，包括 几种疾病内型或潜在的病理生理机制。与该提议相关的是混合 TH2/TH17内型以混合的嗜酸性和嗜中性粒细胞注射为特征 与更难治疗和抗类固醇的哮喘有关。我们最近表明了一个白介素 4受体（IL-4R）变体与严重哮喘相关，IL-4Rα-R576，独特地驱动混合TH2/TH17细胞 气道中的炎症与这种内型哮喘患者紧密地分离。我们进一步确定了 这种变体促进混合Th2/Th17注射的机制涉及IL-4依赖性 过敏原特异性诱导的调节t（ITREG）细胞成Th17细胞样表型，导致它们的表型 变性为真正的过敏原特异性致病性TH17细胞。 IL-4Rα-R576与 严重且难以治疗哮喘，在城市内部小儿年龄哮喘患者中尤为常见。 在比较野生型（Q576/Q576）时，已建立的剂量反应关系与IL-17 突变体（Q576/R576）和纯合（R576/R576）突变等位基因和哮喘发病率。这些观察 提供与抗IL-4R blocade与抗IL-4R单克隆抗体（MAB）dupilumab一起使用的理由 中断依赖IL-4的混合Th2/Th17细胞注入并同时恢复的双重目的 宽容。该提案汇集了在过敏疾病，遗传学和 宽容解决以下假设：携带这种变体的小儿年龄哮喘患者将表现出来 对Dupilumab的特别有利响应，IL-4Rα-R576变体驱动器混合TH2/TH17细胞 通过颠覆过敏原特异性诱导T调节（ITREG）细胞反应，气道中的炎症 进入Th17细胞谱系。我们还将探讨长期宽容的潜力。调查这一点 总体假设这一试验和机械研究由研究人员以其专业知识认可 并有了可靠的合作记录。我们将检查这些临床反应 儿童基于基因型和检查T细胞炎症和调节的演变的治疗 用安慰剂或二吡啶单抗治疗的IL-4R基因型分层的哮喘儿童的反应。 这些研究有望由IL-4Rα-R576指导的精确药物引导的有效疗法 专门针对难以治疗哮喘儿童的疾病驱动内型的基因型。