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Title: Modulation of dendritic cell phenotype and function in asthma
Author: Cameron, Aoife
ISNI:       0000 0004 7228 3476
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Rhinoviruses (RV) are the major cause of asthma exacerbations, with evidence supporting a synergistic relationship between viruses and allergen. Dendritic cells (DCs) mediate airway recognition of both viruses and allergens and instruct downstream immune responses. However, nothing is known about the role of DCs in viral exacerbations of asthma. We hypothesised that following viral infection, asthmatic patients have reduced airway recruitment of anti-viral type II mDCs and pDCs, in addition, these patients exhibited impaired DC anti-viral functionality. To address these hypotheses, moderate atopic asthmatic patients and healthy controls were experimentally infected with RV-16. Bronchoalveolar lavage (BAL) was collected at baseline, day 3 and day 8 post infection and DC populations were isolated and analysed using fluorescence activated cell sorting (FACS). At baseline, the number of type II mDCs, which cross prime CD8+ T cells and induce type I anti-viral responses, was significantly reduced in asthmatic patients. Following RV-16 infection, their recruitment to the airways was delayed compared to healthy controls. No difference in the recruitment of type I mDCs and pDCs was observed. Furthermore, we identified reduced anti-viral interferon reponses in purified peripheral pDCs from asthmatic patients in response to ex vivo RV-16 stimulation. IFN-α production was significantly reduced in asthma patients compared to healthy controls (p=0.028). IFN-λ production was lower in a sub group of asthmatics, although not significantly reduced compared to healthy controls. Deficient IFN-β production was identified in BAL cells from asthmatic patients following ex vivo RV-16 stimulation, compared to healthy controls (p=0.016), with a trend towards reduced IFN- λ. We aim to correlate these findings with clinical parameters, to determine whether deficient cellular recruitment and innate IFN responses have an impact on viral clearance, lung function and both upper and lower airway symptoms. This work will aid our understanding of the pathogenesis of asthma and the role of DCs in viral induced exacerbations.
Supervisor: Johnston, Sebastian ; Walton, Ross Sponsor: Asthma UK ; Medical Research Council ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral