Project 1 Immune Pathway Interactions in Steroid Refractory Severe Asthma

重度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。这种对治疗的总体差异反应 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。在与萨利·温泽尔博士合作进行的人体样本研究中，我们有 观察到大多数(70%-75%)的重症哮喘患者具有显著的Th1(干扰素-γ)适应性免疫 在呼吸道的核糖核酸和蛋白质水平上都有反应，50%的人表现出干扰素-γHiIL-27hi反应。Th1 SA中的签名还伴随着低水平但可检测到的Th2和Th17的存在。这些发现也是 无偏的RNA测序(RNA-SEQ)方法证实了这一点。此外，我们注意到一个严重的 ALL患者支气管肺泡灌洗液或外周血中T细胞产生IL-10的缺陷 严重的哮喘患者。这些结果支持了我们的观点，即SA不能仅被解释为被中介 通过Th2效应细胞，在轻度哮喘中占主导地位。从人体研究中得到的线索，我们一直在 成功地建立了SA的小鼠模型，该模型显示了与我们在 这是一种人类疾病，也是一种在很大程度上对CS没有反应的疾病。 总而言之，我们的数据引导我们假设：1)在大多数重度哮喘患者中，异常的气道 免疫反应不同于以干扰素-γ高表达为特征的轻度哮喘，这是一个关键 严重哮喘(SA)表型的贡献者。患有最严重疾病的患者有一种 IL-27hiIFN-γ在小鼠肺泡灌洗液细胞中的表达。2)SA的第二种免疫反应是IL-10缺乏 从T细胞产生，其一个潜在的机制是增加STAT1的激活。3)结合在一起， 干扰素-γ和IL-27诱导SA对CS不敏感。 为了解决这些假设，我们将： 目的1.确定大多数重症哮喘患者的免疫反应不同于 轻度哮喘患者在呼吸道细胞中表现为干扰素-γ高IL-10lo谱，其亚群也是IL-27HI。 目的2.确定重症哮喘患者IL-10产生缺陷的机制。 目的3.用外周血检测IL-27和干扰素-γ在CS无反应中的作用 单个核细胞(PBMC)。 项目1和项目2之间的协同作用，后者侧重于了解 呼吸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 目前没有得到满足的医疗需求。

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.