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Title: Mechanisms underlying the resolution of HDM induced allergic airways disease
Author: Mathie, Sara A.
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Allergic asthma is a chronic inflammatory disease of the lung and deficiencies in pro-resolving mechanisms may contribute to the persistence of inflammation. The overall aim of this project was to establish a resolution model of house dust mite (HDM) induced allergic airway disease (AAD) and identify mediators of resolution. In our model, features of disease, induced by HDM at peak disease 4 hours, airway hyper-reactivity (AHR), Th2 lymphocytes and eosinophils remained significantly elevated 7 days after last challenge, resolving to baseline by 13 days. The levels of FoxP3+ regulatory lymphocytes also follow this pattern. However, as disease waned there was an elevation in the levels of alveolar macrophages and up regulation of the homeostatic molecule CD200R up to 13 days. Exposure to a single i.n administration of HDM in the resolved airways resulted in a rapid increase in Th2 inflammation and AHR suggesting that after resolution of HDM inflammation there is altered immune homeostasis in the lung. The pro-resolving lipid Lipoxin A4 was induced in the lung by HDM exposure and remained detectable during resolution. Depletion of alveolar macrophages during the resolution phase of allergen challenge resulted in delayed clearance of Th2 lymphocytes, airway neutrophils and interstitial macrophages. Conversely, adoptive transfer of alveolar macrophages during resolution resulted in reduced numbers of lung tissue leukocytes, specifically neutrophils and interstitial macrophages. This suggests a cross talk between these macrophage subsets and a novel interaction for pulmonary homeostasis. The anti-inflammatory peptide Annexin A1 is highly expressed by alveolar macrophages and mice deficient in Annexin A1 had enhanced AHR and Th2 immunity response to HDM. Blocking the Annexin A1 receptor FPR2 enhanced AHR and lung inflammation. Conversely, therapeutic administration of an Annexin A1 mimetic improved AHR and Th2 immunity. These studies demonstrate that Annexin A1: FPR2 pathway may be important in HDM disease and that resolution of allergic airways disease is an active process resulting in altered homeostasis of the lung.
Supervisor: Lloyd, Clare M. ; Hussell, Tracy Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available