Project 1 Immune Pathway Interactions in Steroid Refractory Severe Asthma

严重哮喘属于不同类型的哮喘，原因很简单，不像轻度哮喘

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.