Immunometabolic phenotypes in adult severe asthma and disease progression

摘要 拟议的实验将测试假设：广泛的纵向和免疫代谢 表型分析将促进我们对SA异质性机制的理解， 未来的治疗发展和临床管理策略。具体而言，全面 表型分析将揭示SA患者的不同生物学机制和临床结局， 持续性2型炎症、非2型疾病和消退缺陷。 严重哮喘（SA）的特征是持续的气道炎症、气道高反应性和 尽管使用糖皮质激素，肺功能仍下降。在这里，我们建议延长NHLBI严重哮喘 研究计划（SARP）的平移，纵向机制研究SA。这项纵向研究 设计代表了提供SA内表型稳定性信息的重要“下一步”， 它们与疾病严重程度和进展的关系。 对SA气道炎症的研究揭示了异质性病理生物学。大约50%的 患者的特征是2型（T2）炎症增加;最近的发现导致了新的T2 靶向治疗。仍然持续和迫切需要进一步阐明 SA亚群中不同的病理生物学为危险分层提供分子表型，新的 治疗开发，特别是非T2炎症，以及精确的临床管理。 在过去6年中，SARP招募了大量美国SA患者队列。受试者全面 在基线时进行表征，然后在三年的纵向随访中进行监测， 对SA的临床、结构、功能和免疫代谢紊乱的新见解。在进行中的工作中， 对3年纵向随访的分析确定了3种主要的免疫表型：（1）持续性T2 炎症，（2）间歇性T2炎症和（3）持续性非T2炎症。免疫表型 在陈述时既有相似之处，也有不同之处，在3年的时间里， 纵向跟踪（例如，支气管扩张剂反应性的变化，恶化的风险;见下文）。在 除了肺部特异性炎症外，许多SA患者还存在全身性炎症、代谢功能障碍， 以及解决机制的缺陷。为了解决我们的主要假设，我们提出了一个国家，多中心， 合作研究与机械翻译的方法与4个具体目标，严格和 全面研究SA免疫代谢表型的分子和细胞起源及其 与疾病进展的关系。

Abstract The proposed experiments will test the hypothesis: Extensive longitudinal and immunometabolic phenotyping will advance our understanding of the heterogeneous mechanisms for SA and inform future therapeutic development and clinical management strategies. Specifically, comprehensive phenotyping will reveal distinct biological mechanisms and clinical outcomes for SA patients with persistent type 2 inflammation, non-type 2 disease, and defective resolution. Severe asthma (SA) is characterized by persistent airway inflammation, airway hyper-responsiveness, and decreased lung function despite glucocorticoids. Here, we are proposing to extend the NHLBI Severe Asthma Research Program (SARP) for a translational, longitudinal mechanistic study of SA. This longitudinal study design represents an essential “next step” to provide information on the stability of SA endophenotypes and their relationship to disease severity and progression. Investigation into SA airway inflammation has uncovered heterogeneous pathobiology. Approximately 50% of patients are characterized by increased type 2 (T2) inflammation; discoveries that led recently to new T2 targeted therapies. There remains a continuing and critical need to further elucidate mechanisms underlying the distinct pathobiology in subpopulations of SA to provide molecular phenotyping for risk stratification, new therapeutic development, especially for non-T2 inflammation, and precision clinical management. Over the last 6 years, SARP has recruited a large US cohort of SA patients. Subjects were comprehensively characterized at baseline and then monitored over three years of longitudinal follow up, leading to significant new insights into clinical, structural, functional and immunometabolic disturbances in SA. In work in progress, analyses of 3-year longitudinal follow-up has established 3 principal immunophenotypes: (1) persistent T2 inflammation, (2) intermittent T2 inflammation, and (3) persistent non-T2 inflammation. The immunophenotypes had both similarities and differences at presentation with differences evolving further over 3 years of longitudinal follow up (e.g., changes in bronchodilator responsiveness, risk for exacerbations; vide infra). In addition to lung specific inflammation, many SA patients have systemic inflammation, metabolic dysfunction and defects in resolution mechanisms. To address our main hypothesis, we propose a national, multicenter collaborative study with a mechanistic translational approach with 4 specific aims to rigorously and comprehensively investigate the molecular and cellular origin of SA immunometabolic phenotypes and their relationship to disease progression.