Project 1 Immune Pathway Interactions in Steroid Refractory Severe Asthma

项目 1 类固醇难治性严重哮喘中的免疫途径相互作用

• 批准号: 8853016
• 负责人: Anuradha Ray
• 金额: $ 38.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853016
• 关键词: Address; Adrenal Cortex Hormones; Asthma; Binding; Bioinformatics; Biological Assay; Blood Cells; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Categories; Cells; Clinical; Collaborations; Cues; Data; Defect; Disease; Effector Cell; Epithelial; Epithelial Cells; Follow-Up Studies; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Histone Deacetylase; Hormones; Human; IgE; Image; Imaging Techniques; Immune; Immune response; Immunology; Interferon Type II; Interferons; Interleukin-10; Lead; Lung; Lung Compliance; Mediating; Medical; Methods; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Molecular Profiling; Mononuclear; Mus; Nature; Nuclear Translocation; Oxidative Stress; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Production; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; RNA; RNA Sequences; Refractory; Regulation; Regulatory Element; Respiratory physiology; Role; STAT1 gene; Sampling; Steroids; Stress; T cell response; T-Lymphocyte; Techniques; Technology; Testing; adaptive immunity; airway hyperresponsiveness; asthmatic; asthmatic patient; chromatin immunoprecipitation; clinical phenotype; cytokine; human disease; inhibitor/antagonist; methacholine; mouse model; novel; peripheral blood; response; targeted treatment; tool; transcription factor; transcriptome sequencing

Severe asthma belongs to a different category of asthma for the simple reason that unlike the milder form of the disease it is difficult to control by corticosteroids (CS). This general differential response to therapy between mild and severe asthmatics suggests a difference in the nature of the immune in the two subclasses of asthmatics. In studies of human samples performed in collaboration with Dr. Sally Wenzel, we have observed that the majority (70-75%) of severe asthmatics harbor a prominent Th1 (IFN-γ) adaptive immune response both at RNA and protein levels in their airways and 50% show a IFN-γhiIL-27hi response. The Th1 signature in SA is also accompanied by, a low but detectable, Th2 and Th17 presence. These findings are also corroborated by an unbiased RNA-sequencing (RNA-seq) method. In addition, we have noted a severe deficiency in IL-10 production by T cells in bronchoalveolar lavage (BAL) fluid or in peripheral blood of all severe asthmatics. These results support our contention that SA cannot be explained solely as being mediated by Th2 effector cells, which dominate Th2hi mild asthma. Taking cues from the human studies, we have been successful in establishing a mouse model of SA that displays an immune profile similar to what we observe in human disease and one that is also largely CS-unresponsive. Collectively, our data lead us to hypothesize that: 1) In a majority of severe asthmatics, the aberrant airway immune response is distinct from that in milder asthma characterized by a IFN-γhi profile which is a key contributor to the severe asthma (SA) phenotype. Patients with the most severe form of disease have an IL-27hiIFN-γhi profile in their BAL cells. 2) A second immune response that characterizes SA is deficient IL-10 production from T cells for which one underlying mechanism is increased STAT1 activation. 3) In combination, IFN-γ and IL-27 induce insensitivity to CS in SA. To address these hypotheses we will: Aim 1. Establish that the immune response in the majority of severe asthmatics is distinct from that in milder asthmatics displaying an IFN-γhiIL-10lo profile in airway cells with a subset also being IL-27hi. Aim 2. Determine mechanisms underlying defective IL-10 production in severe asthma. Aim 3. Determine the role of IL-27 plus IFN-γ in CS-unresponsiveness using peripheral blood mononuclear cells (PBMCs). Synergy between Projects 1 and 2, the latter focused on understanding the deleterious consequences of the immune effectors on airway epithelial cells, will identify novel targets for therapy for severe asthma which is currently an unmet medical need.

严重哮喘属于不同类别的哮喘，原因很简单，与轻度哮喘不同 这种疾病很难通过皮质类固醇（CS）来控制，这种治疗反应普遍存在差异。 轻度和重度哮喘患者之间的差异表明这两个亚类的免疫性质存在差异 在与 Sally Wenzel 博士合作进行的人类样本研究中，我们发现 观察到大多数 (70-75%) 严重哮喘患者具有显着的 Th1 (IFN-γ) 适应性免疫系统 呼吸道中的 RNA 和蛋白质水平均出现反应，50% 的人表现出 IFN-γhiIL-27hi 反应。 SA 中的特征还伴随着较低但可检测到的 Th2 和 Th17 的存在。 通过无偏 RNA 测序 (RNA-seq) 方法证实，此外，我们还注意到一个严重的问题。 支气管肺泡灌洗 (BAL) 液或所有外周血中 T 细胞产生 IL-10 的缺陷 这些结果支持我们的观点，即 SA 不能仅仅被解释为是介导的。 Th2 效应细胞主导 Th2hi 轻度哮喘，我们从人体研究中得到启发。 成功建立 SA 小鼠模型，其免疫特征与我们在实验中观察到的相似 人类疾病，也是一种很大程度上对 CS 无反应的疾病。 总的来说，我们的数据使我们认识到：1) 在大多数严重哮喘患者中，异常气道 免疫反应不同于以 IFN-γhi 谱为特征的轻度哮喘，这是关键 导致严重哮喘 (SA) 表型的患者患有最严重的疾病。 2) SA 的第二个免疫反应是缺乏 IL-10 T 细胞的产生，其潜在机制是增加 STAT1 激活 3) 组合起来， IFN-γ 和 IL-27 诱导 SA 对 CS 不敏感。 为了解决这些假设，我们将： 目标 1. 确定大多数严重哮喘患者的免疫反应与普通哮喘患者不同 较轻的哮喘患者在气道细胞中表现出 IFN-γhiIL-10lo 谱，其中一个子集也是 IL-27hi。 目标 2. 确定严重哮喘中 IL-10 产生缺陷的机制。 目标 3. 使用外周血确定 IL-27 加 IFN-γ 在 CS 无反应中的作用 单核细胞（PBMC）。 项目 1 和 2 之间的协同作用，后者侧重于了解项目 1 和项目 2 的有害后果 气道上皮细胞上的免疫效应物，将确定治疗严重哮喘的新靶点 目前尚未满足的医疗需求。