Background: The incidence of asthma is increasing at an alarming rate. While the current available therapies are
effective, there are associated side effects and they fail to adequately control symptoms in all patient subsets. In the
search to understand disease pathogenesis and find effective therapies hypotheses are often tested in animal
models before progressing into clinical studies. However, current dogma is that animal model data is often not
predictive of clinical outcome. One possible reason for this is the end points measured such as antigen-challenge
induced late asthmatic response (LAR) is often used in early clinical development, but seldom in animal model
systems. As the mouse is typically selected as preferred species for pre-clinical models, we wanted to characterise
and probe the validity of a murine model exhibiting an allergen induced LAR.
Methods: C57BL/6 mice were sensitised with antigen and subsequently topically challenged with the same
antigen. The role of AlumTM adjuvant, glucocorticoid, long acting muscarinic receptor antagonist (LAMA), TRPA1,
CD4+ and CD8+ T cells, B cells, Mast cells and IgE were determined in the LAR using genetically modified mice and
a range of pharmacological tools.
Results: Our data showed that unlike other features of asthma (e.g. cellular inflammation, elevated IgE levels and
airway hyper-reactivity (AHR) the LAR required AlumTMadjuvant. Furthermore, the LAR appeared to be sensitive to
glucocorticoid and required CD4+ T cells. Unlike in other species studied, the LAR was not sensitive to LAMA
treatment nor required the TRPA1 ion channel, suggesting that airway sensory nerves are not involved in the LAR
in this species. Furthermore, the data suggested that CD8+ T cells and the mast cell—B-cell - IgE axis appear to be
protective in this murine model.
Conclusion: Together we can conclude that this model does feature steroid sensitive, CD4+ T cell dependent,
allergen induced LAR. However, collectively our data questions the validity of using the murine pre-clinical model
of LAR in the assessment of future asthma therapies.