Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544280
Title: Mechanisms of interleukin-13 inhibition of allergic inflammation
Author: Tomlinson, Kate Louise
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Abstract:
Interleukin-13 (IL-13) is a Th2 cytokine proposed to mediate aspects of asthma pathogenesis such as airway inflammation, hyperreactivity (AHR), remodelling and mucus hypersecretion. These features of asthma have been reproduced in mice chronically exposed to house dust mite extract (HDM) in which IL-13 was demonstrated to be up-regulated. The aim of this thesis was to investigate the role of IL-13 in HDM induced allergic airways disease (AAD). This was accomplished using high affinity neutralising anti-mouse IL-13 monoclonal antibodies (mAb). Prophylactic anti-IL-13 mAb administration during HDM exposure inhibited airway eosinophilia, AHR, goblet cell up-regulation and airway remodelling. Furthermore, therapeutic neutralisation of IL-13 after the induction of AAD reduced airway inflammation, AHR, goblet cell frequency and remodelling; thus implicating IL-13 in both the initiation and maintenance of AAD. To investigate the mechanisms of IL-13 inhibition in AAD the expression and distribution of IL-13 receptors, IL-13Rα1 and IL-13Rα2, were investigated in lungs from sham and HDM exposed mice. IL-13Rα2 but not IL-13Rα1 mRNA was up-regulated following induction of AAD. Immunofluorescence staining for IL-13Rα2 protein revealed expression in the airway epithelium of sham mice and abundance throughout the lung tissue in mice with AAD. The key signalling receptor IL-13Rα1 was detected in alveolar macrophages (AM) in both sham and HDM exposed mice, however surface expression of IL-13Rα1 was lost during AAD. The function of IL-13Rα1+ AM in vivo was explored by depletion of AM using clodronate liposomes. The absence of AM during IL-13 or HDM induced inflammation resulted in exacerbated airway pathophysiology suggesting AM may regulate allergic airways inflammation. In summary, HDM induced pathophysiology in mice is largely dependent on IL-13. Based on receptor expression, AM were identified as IL-13 responsive cells, however AM depletion exacerbated AAD indicating AM, or a subset of, are not driving IL-13 pathology and may in fact be protective.
Supervisor: Lloyd, Clare ; Palframan, Roger Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.544280  DOI: Not available
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