Development of Immunologic Tolerance in a Murine Model of House Dust Mite-Induced Asthma

Allergic asthma is a leading cause of morbidity in industrialized nations and results from lack of immunologic tolerance to environmental antigens. Understanding the factors that contribute to immune tolerance is critical for the development of improved therapeutic strategies for asthma. Although much has been gained from studying ovalbumin (OVA)-induced mouse models of allergic airway disease (AAD), OVA is far less immunologically complex than most human-relevant antigens. House dust mite (HDM) is the most common cause of asthma worldwide. In a novel murine model of AAD, short-term (2 weeks) and intermediate-term (5 weeks) intranasal HDM exposure resulted in classic hallmarks of asthma, including airway eosinophilia and airway hyper-reactivity (AHR). Intriguingly, long-term (11 weeks) HDM instillation resulted in suppression of Th2-mediated disease processes, providing the first evidence of its kind that immunologic tolerance can develop with continuous exposure to a human-relevant allergen. Moreover, HDM-induced tolerance resulted in suppression of disease despite persistent lung inflammation rather than complete resolution of inflammation, which may be more clinically representative of the processes involved with tolerance development in humans. While long-term exposure to both OVA and HDM was associated with increased numbers of local Foxp3+ regulatory T cells (Tregs), only long-term HDM exposure resulted in upregulation of IL-10 production by lung alveolar macrophages (AM). These AMs were found to be capable of inducing Tregs, suggesting that they may play an important role in the suppression of HDM-induced asthma. We believe that this macrophage population may be exploitable for the development of enhanced immunotherapeutic strategies for asthma.