Immune Airway-Epithelial Interactions in Steroid-Refractory Severe Asthma

类固醇难治性严重哮喘中的免疫气道-上皮相互作用

基本信息

批准号：
10425153
负责人：
Anuradha Ray
金额：
$ 187.86万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10425153
关键词：
Address Adrenal Cortex Hormones Air Animal Model Anti-Inflammatory Agents Apoptosis Asthma Bioinformatics Biological Biological Markers Biological Products Bronchoalveolar Lavage CD8-Positive T-Lymphocytes CXCL10 gene Cell Culture System Cell Death Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Characteristics Chemotactic Factors Communication Complex Computer Analysis Cytometry Data Development Disease Disease model Epigenetic Process Epithelial Epithelial Cells Failure Functional disorder Gene Expression Profiling Genetic Glucocorticoid Receptor Guidelines Heterogeneity Human Immune Immune System Diseases Immune response Immunologics Immunosuppression In Vitro Inflammation Inflammatory Inhalation Innate Immune Response Interferon Type II Interferons Interleukin-18 Interleukin-4 Knowledge Laboratories Liquid substance Lymphocyte Memory Molecular Molecular Target Morbidity - disease rate Mucins Natural Immunity Pathogenesis Pathway interactions Patients Peptide Hydrolases Phenotype Process Production Publishing Quality of life Refractory Regulation Research Risk Role STAT1 gene Sampling Signal Transduction Statistical Data Interpretation Steroid Resistance Steroids Stimulus Subgroup Symptoms T cell receptor repertoire sequencing T-Lymphocyte Techniques Therapeutic Time Tissues adaptive immune response adaptive immunity airway epithelium asthmatic asthmatic patient base bronchial epithelium clinical diagnosis cost disorder control experience interest molecular phenotype mouse model multiple omics new therapeutic target novel programs pulmonary function repaired response side effect targeted treatment trait transcriptome sequencing treatment response

项目摘要

Severe asthma (SA) is complex, multifactorial and refractory to treatment by corticosteroids (CS). In recent years, some progress has been made in its treatment with the advent of biologics. However, despite these advancements, there still remain challenges in the treatment of these patients because of an incomplete understanding of the dysfunction of immune and epithelial cells, which underlies this disease. This is further complicated by the poor biomarkers available to differentiate disease for targeted therapy, and amplified by their enormous costs, particularly when prescribed imprecisely. Progress made in Project 1 in the current cycle using mass cytometry/CyTOF, show clustering of SA patients into 2 groups displaying distinct immune profiles divided along the lines of innate and adaptive immunity. Progress made in Project 2 in studies of bronchial epithelial cells (BECs) in SA suggest the presence of two fundamentally different molecular phenotypes. The BECs in one group primarily respond to inhaled environmental stimuli to drive an innate intrinsic phenotype. In the second group, BEC cell death pathways intersect with CD8 T-cell immune processes to drive an immune interactive phenotype. Taken together, these findings prompted us to hypothesize that two distinct immune mechanisms, one regulated by innate immune cells, and the second by T cells, are critical determinants of SA. Interactions between airway epithelial cells in the context of genetic/epigenetic risks and immune cells together with induction of cellular death contribute to two SA phenotypes. This hypothesis will be addressed in the following two highly interactive projects: Project 1 will use human samples and mouse models of disease to: a) characterize the CITE-seq and TCR-seq airway immune cells collected by BAL and investigate the impact of dupilumab on immune phenotype, b) study the importance of FceRI-expressing innate immune cells and IL-7Ra signaling in FceRI+ cells in promoting a SA phenotype using a novel protease-based mouse model, and c) study mechanisms underlying regulation of TRM cell phenotype and impact on disease using a T cell-driven mouse model of SA. Project 2 will use fresh and cultured healthy and asthmatic BECs to: a) determine the mechanisms for and functional implications of an innate intrinsic epithelial phenotype, b) evaluate the role of GSDMB in the development of a CD8 T-cell immune interactive phenotype and its functional implications, and c) Integrate immune-inflammatory phenotypes with epithelial molecular phenotypes ex vivo and in vitro. Synergistic interactions among projects will be afforded by support from: Core A, the Administrative Core, to coordinate the activities of the Program Project at all levels, Core B, the Human Biological Sampling and Immunocytometry Core and Core C, the RNA-Seq and Bioinformatics Core. Taken together, these projects will establish new concepts in immune- epithelial interactions underlying asthma pathogenesis and identify novel targets for therapy.

严重哮喘（SA）是一种复杂的、多因素的疾病，并且皮质类固醇（CS）难以治疗。近来多年来，随着生物制剂的出现，其治疗取得了一些进展。然而，尽管有这些尽管取得了进展，但由于不完全的治疗，这些患者的治疗仍然存在挑战了解导致这种疾病的免疫和上皮细胞功能障碍。这进一步由于可用于区分疾病进行靶向治疗的不良生物标志物使情况变得复杂，并且通过其巨大的成本，特别是在规定不精确的情况下。目前项目1取得的进展使用质谱流式细胞仪/CyTOF 进行循环，显示 SA 患者分为 2 组，显示出不同的免疫概况按照先天免疫和适应性免疫划分。项目2研究取得进展 SA 中的支气管上皮细胞 (BEC) 表明存在两种根本不同的分子表型。一组中的 BEC 主要对吸入的环境刺激做出反应，以驱动先天的内在表型。在第二组中，BEC 细胞死亡途径与 CD8 T 细胞免疫交叉驱动免疫相互作用表型的过程。总而言之，这些发现促使我们假设有两种不同的免疫机制，一种由先天免疫细胞调节，另一种由 T 细胞是 SA 的关键决定因素。气道上皮细胞之间的相互作用遗传/表观遗传风险和免疫细胞以及细胞死亡的诱导导致两种SA 表型。这一假设将在以下两个高度互动的项目中得到解决：项目 1 将使用人类样本和小鼠疾病模型来：a) 表征 CITE-seq 和 TCR-seq 气道通过 BAL 收集免疫细胞并研究 dupilumab 对免疫表型的影响，b) 研究表达 FceRI 的先天免疫细胞和 FceRI+ 细胞中的 IL-7Ra 信号传导在促进 SA 中的重要性使用基于新型蛋白酶的小鼠模型来表型，以及c）研究潜在调节机制使用 T 细胞驱动的 SA 小鼠模型研究 TRM 细胞表型及其对疾病的影响。项目2将使用新鲜并培养健康和哮喘 BEC，以： a) 确定 BEC 的机制和功能影响先天内在上皮表型，b) 评估 GSDMB 在 CD8 T 细胞发育中的作用免疫相互作用表型及其功能意义，以及 c) 整合免疫-炎症表型与离体和体外上皮分子表型。项目之间的协同互动将得到以下支持：核心 A，行政核心，协调该计划的活动各个级别的项目，核心 B、人类生物采样和免疫细胞术核心和核心 C、 RNA-Seq 和生物信息学核心。总而言之，这些项目将在免疫领域建立新概念上皮相互作用是哮喘发病机制的基础，并确定新的治疗靶点。