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Title: Mechanisms underlying the immune response to inhaled house dust mite
Author: Causton, Benjamin
ISNI:       0000 0004 2711 6345
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Asthma is a chronic inflammatory disease of the airways and is characterised by airway hyperresponsiveness (AHR), inflammation and remodelling. House dust mite (HDM; Dermatophagoides pteronyssinus) is a complex aeroallergen, commonly associated with development of allergic asthma. Animal models have been utilised extensively to model the traits of asthma and HDM-induced allergic airways disease was established in mice following serial HDM challenge via the respiratory mucosa. Mice exposed to HDM developed pulmonary eosinophilia, characterised by Th2 cytokine production, concomitant with AHR and airway remodelling. Following the establishment and characterisation of this model of allergic airways disease, it was next investigated which features of the HDM allergen were responsible for disease pathogenesis. Using genetically modified mice and pharmacological approaches, it was found that the TLR-TRIF signalling pathway played a crucial role in HDM-induced allergic airways disease. Intrinsic protease activity of the HDM extract was also observed to be vital for disease pathogenesis, whereby mice exposed to boiled HDM developed a less severe asthma phenotype. Utilising a pan neutralising antibody directed towards transforming growth factor-β (TGF-β), TGF-β was shown to play a critical role in regulating HDM-induced airway inflammation in vivo. Following therapeutic blockade of TGF-β, the numbers of CD4+CD25+FoxP3+ regulatory T cells and CD4+IL-10+ cells were decreased resulting in exacerbation of AHR and BAL inflammation compared to HDM-treated isotype control mice. However, HDM-induced airway remodelling progressed independently of TGF-β. In conclusion, it has been determined that HDM-induced Th2-driven inflammation, AHR and airway remodelling in mice is induced by multiple features of the allergen and that TGF-β regulates HDM-driven airway inflammation. Thus these findings provide an insight into the mechanisms by which the aeroallergen HDM promotes allergic disease and will aid in the development of potential new therapeutic strategies for the treatment of asthma.
Supervisor: Lloyd, Clare ; Gregory, Lisa Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral