Immune Airway-Epithelial Interactions in Steroid-Refractory Severe Asthma

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Severe asthma (SA) is complex, multifactorial and refractory to treatment by corticosteroids (CS). In recent years, some progress has been made in its treatment with the advent of biologics. However, despite these advancements, there still remain challenges in the treatment of these patients because of an incomplete understanding of the dysfunction of immune and epithelial cells, which underlies this disease. This is further complicated by the poor biomarkers available to differentiate disease for targeted therapy, and amplified by their enormous costs, particularly when prescribed imprecisely. Progress made in Project 1 in the current cycle using mass cytometry/CyTOF, show clustering of SA patients into 2 groups displaying distinct immune profiles divided along the lines of innate and adaptive immunity. Progress made in Project 2 in studies of bronchial epithelial cells (BECs) in SA suggest the presence of two fundamentally different molecular phenotypes. The BECs in one group primarily respond to inhaled environmental stimuli to drive an innate intrinsic phenotype. In the second group, BEC cell death pathways intersect with CD8 T-cell immune processes to drive an immune interactive phenotype. Taken together, these findings prompted us to hypothesize that two distinct immune mechanisms, one regulated by innate immune cells, and the second by T cells, are critical determinants of SA. Interactions between airway epithelial cells in the context of genetic/epigenetic risks and immune cells together with induction of cellular death contribute to two SA phenotypes. This hypothesis will be addressed in the following two highly interactive projects: Project 1 will use human samples and mouse models of disease to: a) characterize the CITE-seq and TCR-seq airway immune cells collected by BAL and investigate the impact of dupilumab on immune phenotype, b) study the importance of FceRI-expressing innate immune cells and IL-7Ra signaling in FceRI+ cells in promoting a SA phenotype using a novel protease-based mouse model, and c) study mechanisms underlying regulation of TRM cell phenotype and impact on disease using a T cell-driven mouse model of SA. Project 2 will use fresh and cultured healthy and asthmatic BECs to: a) determine the mechanisms for and functional implications of an innate intrinsic epithelial phenotype, b) evaluate the role of GSDMB in the development of a CD8 T-cell immune interactive phenotype and its functional implications, and c) Integrate immune-inflammatory phenotypes with epithelial molecular phenotypes ex vivo and in vitro. Synergistic interactions among projects will be afforded by support from: Core A, the Administrative Core, to coordinate the activities of the Program Project at all levels, Core B, the Human Biological Sampling and Immunocytometry Core and Core C, the RNA-Seq and Bioinformatics Core. Taken together, these projects will establish new concepts in immune- epithelial interactions underlying asthma pathogenesis and identify novel targets for therapy.