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Title: IL-17 modulation of rhinovirus-induced allergic airways disease
Author: Peel, Tamlyn Jolyon Robert
ISNI:       0000 0004 5349 5916
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Asthma is a chronic inflammatory disease of the airways, resulting in significant morbidity and premature deaths. Rhinoviruses, agents of the common cold, have been identified as the most frequent viruses inducing asthma exacerbations. However the mechanisms involved in this process, especially in moderate-to-severe asthmatics, are not clear. IL-17, a protein secreted by Th17 and IL-17+γδ T cells, is found to be up-regulated in asthmatics and correlates with severity of disease. Observations from a clinical study of rhinovirus infection showed increased induction of IL-17 in nasal lavage fluid from asthmatics following experimental rhinovirus infection compared to healthy controls. Using mouse models, this thesis addresses the interactions of rhinovirus with IL-17 in the context of allergic airways disease. Primary infection of C57BL/6 mice did not induce IL-17 responses as seen in human subjects; this may be explained by the apparent lack of induction of IL-23 following primary infection in mice. Supplementation of rhinovirus infection with recombinant IL-17 showed significant, selective increases in neutrophil chemokines with subsequent increases in both neutrophil recruitment and activation, as defined by myeloperoxidase activity. In an existing Th2-driven model of allergic airways disease, rhinovirus was seen to selectively expand Th2 responses while not increasing allergen-induced Th17, IL-17+γδ T cells or IL-17. However, rhinovirus infection in a Th17-driven model of allergic airways disease showed a significant increase of neutrophil numbers with a concomitant increase in airway hyperresponsiveness. This work augments existing knowledge on rhinovirus exacerbation of Th2-mediated asthma with the interactions between Th17 and rhinovirus, which may play a significant role in moderate-to-severe asthma exacerbations. This supports current research on therapeutic targeting of the IL-17 pathway in asthmatics.
Supervisor: McLean, Gary ; Noble, Alistair ; Johnston, Sebastian Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available