Understanding Severe Asthma Using an Experimental Model

描述（由申请人提供）：严重哮喘是一种难以通过皮质类固醇（CSs）控制的疾病，这仍然是哮喘治疗的主流。这种对CS治疗反应的差异结果，即使在高剂量口服或肠外使用时，表明两种亚类哮喘患者炎症反应的本质存在根本差异。为了了解促进cs难治性哮喘的机制和介质，我们开发了一种疾病小鼠模型，其中气道炎症和cs无反应性模拟了人类的严重哮喘表型，包括高IFN-？/Th1， IL-27和IL-17的反应。我们的模型涉及将小鼠暴露于过敏原（屋尘螨- hdm）和粘膜佐剂环二-GMP (c-二-GMP)，以促进气道中的混合粒细胞浸润，诱导显著升高的IFN-？和IL-17的反应

DESCRIPTION (provided by applicant): Severe asthma is a difficult disease to control by corticosteroids (CSs), which remain the mainstay of asthma therapy. This differential outcome in response to CS therapy, even when used at a high dose orally or parenterally, suggests a fundamental difference in the nature of the inflammatory response in the two subclasses of asthmatics. To understand the mechanisms and mediators that promote CS-refractory asthma, we have developed a mouse model of disease in which both airway inflammation and CS-unresponsiveness mimic the severe asthma phenotype in humans including high IFN-?/Th1, IL-27 and IL-17 responses. Our model involves exposure of mice to an allergen (house dust mite-HDM) with a mucosal adjuvant, cyclic-di- GMP (c-di-GMP), to promote a mixed granulocytic infiltration in the airways with induction of significantly higher IFN-? and IL-17 responses in the lung-draining lymph nodes and the lungs of the mice but a lower IL-13/IL-5 response compared to that induced by HDM alone. Administration of the CS, dexamethasone (Dex), in HDM+c-di-GMP-exposed mice did not subdue the IFN-?/IL-17/IL-13 response or the airway neutrophilia but partially attenuated the eosinophilia. Airway hyperreactivity in these mice was also only partially attenuated by CS. Collectively, our data lead us to hypothesize that 1) CS-refractory asthma is orchestrated by a high Th1 response often accompanied by a Th17 response that promotes airway neutrophilia. 2) Increased production of key Th1- and Th17-skewing cytokines such as IL-27 and IL-12 (Th1) and IL-6 and IL-23 (Th17) from innate cells such as dendritic cells (DCs) underlies the heightened Th1 and Th17 response. 3) The transcription factors IRF5, recently implicated in IL-6, IL-12 and IL-23 production from M1 macrophages, and STAT1, downstream of IFNs and IL-27, are involved in driving Th1 and Th17 development. The idea that CS refractory severe asthma might involve collaboration between IFN-?, IL-27 and Th17 cytokines in severe asthma has not been appreciated or investigated in prior studies. To address our hypotheses we will: Aim 1. Investigate the role of the Th1 and Th17 pathways in promoting the CS-refractory severe asthma phenotype characterized by mixed granulocytic airway inflammation. Aim 2. Determine the mechanisms by which high Th1 and Th17 responses are induced by exposure to HDM and c-di-GMP via effects on innate cells. Aim 3. Identify the cellular source and role of IL-27 in initiation and perpetuation of CS-refractory severe asthma phenotype. The mouse model in conjunction with genetically engineered mice will allow us to investigate the role of key mediators in promoting the severe asthma phenotype. The model will be useful to test novel therapeutic modalities as and when they become available. Additionally, RNA sequencing data generated from this study will identify novel networks in SA for future interrogation in the experimental model and in translational studies.