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Title: The role of IL-25 in rhinovirus-induced asthma exacerbations
Author: Beale, Janine Elizabeth
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Rhinovirus (RV) infections are the principal cause of asthma exacerbations. While Th2-mediated inflammation is clearly implicated in the asthmatic response, it is unknown how the immune response to RV infection interacts with Th2 immunity to enhance disease pathogenesis. The epithelial-derived cytokine, IL-25, has been identified as an initiator and regulator of Th2 immunity and plays a role in asthma pathogenesis. Based on the fact that RV infects bronchial epithelial cells, we hypothesized that RV induces IL-25 production providing a link between infection and Th2 driven allergic inflammation. RV-induced IL-25 expression was measured in human bronchial epithelial cells (HBECs) obtained from bronchoscopic brushings from atopic asthmatics and healthy patients. Mouse models of RV infection and RV-induced allergic airways disease were also employed to examine IL-25 induction in response to RV infection and/or OVA sensitisation and challenge. Finally, to define a mechanistic role for RV-induced IL-25, signalling mediated by IL-25 was blocked in our model of RV-induced allergic airways disease by neutralising the IL-25 receptor. RV-infected HBECs from asthmatics expressed significantly greater IL-25 gene and protein compared with cells from healthy controls. Furthermore, RV infection of mice induced IL-25 expression in the airway epithelium as well as in inflammatory cells in the airway lamina propia. Using a mouse model of RV-induced allergic disease, we demonstrated that RV enhanced allergen-driven IL-25 gene and protein expression which was associated with increased Th2 inflammation in the lung. Finally, by blocking IL-25 signalling in an RV-infected and OVA-sensitised and challenged mouse, several key features of the exacerbation phenotype were significantly reduced including airway leukocyte infiltration, BAL Th2 cytokines and chemokines and Th2 cells. These novel findings indicate that RV-induced IL-25 plays an important role in enhancing Th2 inflammation associated with the exacerbation phenotype which is mediated by binding to the IL-25 receptor.
Supervisor: Bartlett, Nathan ; Johnston, Sebastian Sponsor: National Heart and Lung Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available