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.