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， 皮质类固醇（CS）难以控制的疾病。这种对治疗的一般差异反应 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不同， 哮喘患者的症状在与Sally Wenzel博士合作进行的人体样本研究中，我们 观察到大多数（70-75%）严重哮喘患者具有显著的Th 1（IFN-γ）适应性免疫 结果显示，50%的患者在其气道中的RNA和蛋白质水平均显示IFN-γhiIL-27 hi应答，50%的患者显示IFN-γhiIL-27 hi应答。所述th 1 SA中的特征还伴随着低但可检测的Th 2和Th 17的存在。这些发现也 通过无偏RNA测序（RNA-seq）方法证实。此外，我们注意到， 所有人支气管肺泡灌洗液（BAL）或外周血中T细胞产生IL-10的缺陷 严重的哮喘这些结果支持我们的论点，SA不能被解释为仅仅是介导的 由Th 2效应细胞，其中占主导地位的Th 2 hi轻度哮喘。从人类研究中得到启示，我们一直在 成功地建立了SA小鼠模型，该模型显示出与我们在 人类疾病和一个也是很大程度上对CS无反应的疾病。 总的来说，我们的数据使我们假设：1）在大多数严重哮喘患者中， 免疫应答不同于以IFN-γ高表达谱为特征的轻度哮喘， 严重哮喘（SA）表型的贡献者。患有最严重形式疾病的患者 IL-27hiIFN-γhi谱。2)SA的第二个特征性免疫应答是缺乏IL-10 从T细胞产生，其一个潜在机制是增加STAT 1活化。3)在组合中， 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应答与 在气道细胞中显示IFN-γhiIL-10 lo谱的轻度哮喘患者，其亚群也是IL-27 hi。 目标二。确定严重哮喘中IL-10产生缺陷的潜在机制。 目标3。用外周血确定IL-27和IFN-γ在CS无反应性中的作用 单核细胞（PBMC）。 项目1和项目2之间的协同作用，后者侧重于了解 气道上皮细胞的免疫效应物，将确定治疗严重哮喘的新靶点， 目前尚未满足的医疗需求。