The Influence of Mepolizumab on Structural and Inflammatory Cells in Severe Eosinophilic Asthma

IRIS is a prospective observational study investigating Mepolizumab in the treatment of severe eosinophilic asthma. Eosinophilic airway inflammation has been implicated in the pathogenesis of asthma and is particularly relevant in severe eosinophilic asthma (SEA), in which standard asthma therapies fail to adequately control the disease. In severe asthma, there is bronchial epithelial damage and loss of tight junction integrity, goblet cell hyperplasia, enhanced collagen generation within the airway wall and impaired innate immune responses. Mepolizumab has been shown to reduce exacerbations and improve disease control in SEA but there are no studies assessing the impact of Mepolizumab on structural airway cell activity and function and airway remodelling processes. Primary Objective: To investigate changes within bronchial epithelial cells following completion of 6 months (7 doses) of Mepolizumab using single cell RNA sequencing (scRNA-seq) and Frac-seq (subcellular fractionation and RNA-sequencing). Secondary Objectives: To investigate the following after completing treatment with 6 months of Mepolizumab: i) Changes in epithelial barrier integrity using Frac-seq, transepithelial resistance ii) Changes in epithelial antiviral responses fusing Frac-seq in unstimulated and virus-infected cells. iii) Changes in airway remodelling by assessing the profile of fibroblasts isolated from bronchial biopsies employing Frac-seq and immunostaining of bronchial biopsies iv) Evaluate the impact on peripheral airways by obtaining bronchoalveolar lavage (BAL) and peripheral airway brushings for Frac-seq analysis and protein analysis v) Peripheral airway dysfunction using impulse oscillometry vi) Changes in fibroblast profile with stimulation and IL-5 inhibition using a range of molecular, cellular, protein and metabolic techniques Exploratory Objectives i) Evaluation of neural structural changes using biopsies