Airway Th2Th17 Cells in Refractory Asthma

难治性哮喘中的气道 Th2Th17 细胞

基本信息

批准号：
9029107
负责人：
Rafeul Alam
金额：
$ 44.68万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-20 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029107
关键词：
Accounting Address Antibodies Asthma Biological Markers Biopsy Blood Bronchoalveolar Lavage Cell Nucleus Cells Characteristics Clinical Clinical Trials Complement Complex Consensus Development Direct Costs Disease Event Failure Fc Receptor Flow Cytometry Generations Glucocorticoid Receptor Health Histone Deacetylase IL17 gene IL4 gene IL5 gene IL8 gene IRF4 gene Immunologics Infection Inflammation Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Interleukin-13 Knowledge Link Lung MAP Kinase Gene MAPK14 gene MEKs Marketing Measures Molecular Morbidity - disease rate Pathogenesis Patients Pattern Pharmaceutical Preparations Phenotype Phosphorylation Physiological Play Population Procedures Production Refractory Regulation Reporting Role Signal Transduction Signaling Molecule Steroid Resistance Steroids Subgroup Surface Surrogate Markers Th2 Cells Therapeutic Therapeutic Agents Therapeutic Trials Tissues Work anakinra asthmatic patient base chemokine cytokine mortality neutrophil novel p38 MAPK Signaling Pathway periostin prevent research study success targeted treatment transcription factor transcriptome transcriptome sequencing transdifferentiation treatment response

项目摘要

ABSTRACT Refractoriness to treatment is a major cause of asthma-related morbidity and mortality. Refractory asthma accounts for the bulk of the direct cost for asthma. There is a general consensus that asthma is heterogeneous and that the same treatment will not work for all. Treatments that failed in general asthma population were found beneficial to a specific endotype of asthma (e.g. anti-IL5 antibody in eosinophilic asthma). For this reason identification of mechanism-based subtypes (endotypes) of asthma and development of mechanism-targeted treatment are of paramount importance. Using flow cytometry-based characterization of bronchoalveolar lavage (BAL) cells we have recently reported the identification of a novel endotype of asthma that is characterized by the dominance of dual positive Th2/Th17 cells in the airways. This Th2/Th17 predominant endotype distinguishes itself from the Th2 predominant and Th2/Th17 low endotypes with more severe asthma and greater refractoriness to treatment including steroids. The objective of this proposal is to study this Th2/Th17 predominant endotype of severe refractory asthma. We propose 4 specific aims. Under specific aim 1 we will characterize dual positive Th2/Th17 cells in airways from asthmatic patients and define the phenotype of Th2/Th17 predominant asthma. We will perform bronchoalveolar lavage, endobronchial biopsy and brushing in refractory asthmatic patients. We will characterize the cytokine and surface marker profile of BAL Th2/Th17 cells by flow cytometry and RNA-seq. Through analyses of tissue histopathologic, pulmonary physiologic, immunologic & clinical features we will identify unique phenotypic characteristics that are associated with the production of Th17 cytokines by Th2/Th17 cells. Specific aim 2 will examine the mechanism of development of airway Th2/Th17 cells in asthma. We will examine the role of IL1β and danger-associated molecular patterns in transdifferentiation of Th2 cells into Th2/Th17 cells. Under specific aim 3 we will delineate the signaling mechanism of steroid resistance of Th2/Th17 cells. The cytokines that induce Th2/Th17 cells also activate the MEK and p38 MAPK signaling pathways. We will examine the role of these signaling molecules in induction of steroid resistance. We will examine MEK regulation of the glucocorticoid receptor-associated co-repressor SMRT, p38 regulation of glucocorticoid receptor phosphorylation, and the consequences of these events for steroid resistance. Specific aim 4 will examine the role of IL1α and IL8 in the pathogenesis of neutrophilic asthma, another steroid resistant form of refractory asthma. We will also examine the role of Th2 cytokines in preventing neutrophil influx into the airways in Th2/Th17 predominant asthma. The study is important because it identifies and characterizes a novel endotype of severe refractory asthma. We will perform invasive procedures and examine bronchoalveolar lavage cells and bronchial tissue for vast majority of experiments, which has direct relevance for asthma. The delineation of the molecular mechanism of Th2/Th17 cell development and its steroid resistance will pave the way for clinical trials of already existing therapeutic agents in Th2/Th17 endotype of severe refractory asthma.

抽象的难治性哮喘治疗是哮喘相关发病率和死亡率的主要原因。占哮喘直接费用的大部分人们普遍认为哮喘是一种疾病。异质性，同样的治疗方法并不适用于所有治疗普通哮喘的患者。发现人群对哮喘的特定内型有益（例如嗜酸性粒细胞中的抗 IL5 抗体）因此，需要识别哮喘的基于机制的亚型（内型）。使用基于流式细胞术的机制靶向治疗的发展至关重要。支气管肺泡灌洗 (BAL) 细胞的表征我们最近报道了一种新型的鉴定哮喘的内型，其特征是气道中双阳性 Th2/Th17 细胞占主导地位。 Th2/Th17 优势内型与 Th2 优势和 Th2/Th17 低内型不同患有更严重的哮喘和对包括类固醇在内的治疗更难治的患者。建议是研究这种以Th2/Th17为主的严重难治性哮喘的内型。我们提出了4个具体的方案。在具体目标 1 下，我们将表征哮喘患者气道中的双阳性 Th2/Th17 细胞。并确定 Th2/Th17 为主的哮喘表型我们将进行支气管肺泡灌洗，我们将在难治性哮喘患者中进行支气管内活检和刷检来表征细胞因子和。通过流式细胞术和 RNA-seq 分析 BAL Th2/Th17 细胞的表面标志物谱。组织病理学、肺部生理学、免疫学和临床特征，我们将识别独特的表型与 Th2/Th17 细胞产生 Th17 细胞因子相关的特征 2 将。检查气道 Th2/Th17 细胞在哮喘中的发育机制我们将检查 IL1β 的作用。 Th2 细胞转分化为 Th2/Th17 细胞时的危险相关分子模式。具体目标 3 我们将描述 Th2/Th17 细胞类固醇抵抗的信号传导机制。诱导 Th2/Th17 细胞也激活 MEK 和 p38 MAPK 信号通路的作用我们将检查其作用。我们将研究 MEK 对类固醇抗性的调节作用。糖皮质激素受体相关辅阻遏物 SMRT、p38 对糖皮质激素受体的调节磷酸化，以及这些事件对类固醇抵抗的影响。具体目标 4 将检查 IL1α 和 IL8 在中性粒细胞性哮喘发病机制中的作用，中性粒细胞性哮喘是另一种类固醇耐药的难治性哮喘我们还将研究 Th2 细胞因子在防止中性粒细胞流入气道中的作用。这项研究很重要，因为它确定并描述了一种新型哮喘。严重难治性哮喘的内型我们将进行侵入性手术并检查支气管肺泡。绝大多数实验使用灌洗细胞和支气管组织，这与哮喘有直接关系。阐明 Th2/Th17 细胞发育及其类固醇抗性的分子机制将为对现有治疗药物治疗重度难治性哮喘 Th2/Th17 内型进行临床试验的方法。