Abstract
BackgroundThe 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.MethodsC57BL/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.ResultsOur 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.ConclusionTogether 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.
Highlights
The incidence of asthma is increasing at an alarming rate
Prior to investigating a role for various key allergic effector cells in the late asthmatic response (LAR) response we evaluated the phenotype of the CD4−/−, CD8−/−, B-cell−/− and mastcell−/− mice using flow cytometry and histology
In summary, explorations of the murine model of LAR demonstrated that the response was induced by allergen challenge, steroid sensitive and T-cell dependant
Summary
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. Patients generally present with a history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation [1,2,3,4] It affects approximately 300 million people worldwide and the World Health Organisation estimates asthma to. Studies so far exploring this particular feature of asthma have concluded that it is likely that the LAR is at least in part driven by inflammation This conclusion is largely based on the fact that the response is accompanied by cellular inflammatory influx into the lung along with the demonstration that steroid treatment impacts on the response [16, 17]. Others have suggested alternative mechanisms behind the LAR such as a possible role for airway sensory nerves [18]
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