Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

Abstract

Background: Allergic asthma is a major cause of worldwide morbidity and results from inadequate immune regulation in response to innocuous, environmental antigens. The need exists to understand the mechanisms that promote nonreactivity to human-relevant allergens such as house dust mite (HDM) in order to develop curative therapies for asthma. The aim of our study was to compare the effects of short-, intermediate- and long-term HDM administration in a murine asthma model and determine the ability of long-term HDM exposure to suppress allergic inflammation. Methods: C57BL/6 mice were intranasally instilled with HDM for short-term (2 weeks), intermediate-term (5 weeks) and long-term (11 weeks) periods to induce allergic airway disease (AAD). The severity of AAD was compared across all stages of the model via both immunological and pulmonary parameters. Results: Short- and intermediate-term HDM exposure stimulated the development of AAD that included eosinophilia in the bronchoalveolar lavage fluid (BALF), pronounced airway hyperreactivity (AHR) and evidence of lung inflammation. Long-term HDM exposure promoted the suppression of AAD, with a loss of BALF eosinophilia and AHR despite persistent mononuclear inflammation in the lungs. Suppression of AAD with long-term HDM exposure was associated with an increase in both Foxp3+ regulatory T cells and IL-10-positive alveolar macrophages at the site of inflammation. Conclusions: This model recapitulates the key features of human asthma and may facilitate investigation into the mechanisms that promote immunological tolerance against clinically relevant aeroallergens.

Acetaminophen Attenuates House Dust Mite-Induced Allergic Airway Disease in Mice

“…Therefore, the objective of this study was to evaluate the effects of APAP in a murine HDM model of allergic airway disease. HDM produced a robust and dose-dependent increase in inflammation as measured by increased airway eosinophilia and neutrophilia, similar to that observed by other investigators using HDM models (Cates et al, 2004;Bracken et al, 2015). An approximately 2-fold increase in airway macrophages was consistently observed in our model; however, the change was not uniformly detected as statistically significant.…”

“…Initial studies were aimed at defining the dose-response relationships for HDM to delineate both a minimally and maximally effective dose. Based on previous studies, five dose levels ranging from 0.625 to 10 mg were used (Bracken et al, 2015). Mice were administered HDM intranasally once daily for 2 weeks with a 2-day rest period in between weeks 1 and 2.…”

“…The response to HDM in mice exhibits several of the principle features of allergic disease in humans, and importantly HDM produces a respiratory allergic response in mice that has been extensively characterized (Cates et al, 2004(Cates et al, , 2007Johnson et al, 2004;Maes et al, 2010). Immunologic tolerance in HDM models has been shown to occur after long-term exposure (Bracken et al, 2015). Therefore, our studies were limited to 2 weeks in duration and designed to examine changes in the early response to both minimal and maximal doses of HDM.…”

“…Based on the exposure protocol of Bracken et al (2015), equal parts of Dermatophagoides pteronyssinus and Dermatophagoides farinae lyophilized HDM extracts (Greer Laboratories, Lenoir, NC) were resuspended in phosphate-buffered saline at concentrations from 12.5 to 200 ng/dry weight/ml. The lyophilized HDM extract mixture contained 3131 endotoxin units/mg of HDM, and 3.32% D. pteronyssinus/ D. farina, and the same lot number was used throughout the experiments.…”

“…Detection of serum HDM-specific IgE and IgG was performed as described previously (Bracken et al, 2015). Briefly, Nunc MaxiSorp, flat-bottom plates (Thermo Scientific, Waltham, MA) were coated with 10 or 2 mg/ml of HDM extract in sodium bicarbonate buffer (pH 9.5) for IgE or IgG, respectively.…”