Do the current house dust mite-driven models really mimic allergic asthma?
- *Respiratory Pharmacology Group, Pharmacology and Toxicology Section, Imperial College, National Heart and Lung Institute, London, UK
- #Laboratory of Allergology and Pulmonary Diseases, Dept of Pathology and Medical Biology, University Medical Centre Groningen (UMCG), Groningen University, Groningen, The Netherlands
- M.A. Birrell, Respiratory Pharmacology Group, Pharmacology and Toxicology Section, National Heart and Lung Institute, Imperial College School of Medicine, Sir Alexander Fleming Building, Exhibition Road, London, SW7 2AZ, UK. E-mail: m.birrell{at}imperial.ac.uk
To the Editors:
Animal models play a key role in helping us determine the pathogenesis of diseases, and are vital for the discovery of new therapies and the improvement of existing medication. To do this, the model(s) need to closely mimic the clinical features and, where possible, be relevant to the disease in humans. Classically, the innocuous antigen ovalbumin (OVA) has been used to induce an allergic reaction in animals, and whilst it is possible to reproduce many of the features of the asthmatic lung, i.e. specific immunoglobulin (Ig)E levels, T-helper cell (Th)2-associated eosinophilic inflammation, early and late asthmatic responses (EAR and LAR, respectively), and airway hyperresponsiveness and associated tissue remodelling, researchers began to question the clinical relevance of using OVA as a model allergen 1. In addition, it was commonly felt that the need for systemic delivery of OVA, with an adjuvant such as aluminium hydroxide, did not correctly mimic how asthmatic patients become sensitised to aeroallergens. To circumvent these issues, researchers switched to using topically delivered house dust mite allergen (HDM) to model allergic asthma 1, a route that, incidentally, is reported to induce tolerance when using OVA 2, 3. A large proportion of human asthmatic patients have elevated levels of HDM-specific IgE and, after challenge with HDM, exhibit EAR, LAR and increases in airway inflammation 4–7. For these reasons, the choice of HDM as the allergen to use in animal models seems like a logical one and explains the almost unilateral decision to switch to using them. Generally, these models are based around administering HDM topically into the airways, normally via the intranasal route, daily, over multiple weeks. This results in airway inflammation which features an increase in eosinophilia. However, a source of concern is the lack of evidence to show that the inflammation is part of an allergic (i.e. presence of HDM-specific IgE, B-cells and T-cells) phenotype. Unlike the classical OVA model, where, without prior sensitisation, airway inflammation is absent upon challenge, it is not clear whether HDM-induced inflammation is a truly allergic response or merely a consequence of repeated nasal insult with an inflammatory concoction. Indeed, it is possible to induce airway eosinophilia using a variety of non-IgE-associated stimuli, i.e. with Sephadex and endotoxin 8, 9.
The current dogma suggests that the line between “sensitisation” and “challenge” phases is blurred in the repeated HDM insult models. But yet, if these models do have a strong allergic component one would expect more reports of the classical allergic asthma phenotypes, such as increased HDM-specific IgE and respiratory symptoms, such as EAR and LAR. In contrast to the OVA–aluminium hydroxide models that show high serum levels of specific IgE and antigen-induced mast cell degranulation (the prototypic type I hypersensitivity response), most studies using HDM models have either not measured specific IgE levels or have reported a very weak (approximately two-fold increase in optical density) total or specific IgE response. Whereas in patients with HDM allergic asthma, serum levels of specific IgE are usually 100-fold higher compared to non-allergic (<0.35 kU·L−1) controls. What is more, if one uses the presence of specific IgG1 as a marker of HDM-specific B- and T-cell clonal expansion, it would appear that this event occurs after much of the airway inflammation is observed (i.e. interleukin (IL)-5 and IL-13 production, and airway eosinophilia) 10. Studying the role of the key allergic asthma effector cells should help us to understand the mechanisms driving the repeat HDM challenge model. As yet, however, there are only limited reports on the role of cells, such as the mast cell, dendritic cell, B-cell and the Th2-cell in these modelling systems. In addition, to recapture some of the allergic asthma phenotypes currently missing from the repeat HDM challenge models, we suggest it may be necessary to revert to using a systemic sensitisation phase prior to HDM challenge.
Animal models play a key role in helping us to determine the pathogenesis of diseases and are vital for discovery of new therapies. However, we suggest one needs to understand the modelling systems used, what limitations they have and how relevant they are to the human disease before they are utilised in the search for new therapeutic entities. It could well be that repeated topical HDM challenge does adequately model allergic asthma but equally we, as a community, could end up developing a therapy for HDM-induced airway inflammation in rodents rather than a therapy to combat human disease.
Footnotes
Statement of Interest
None declared.
- ©ERS 2010