Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure

Abstract

Murine models of acute atopic asthma may be inadequate to study the effects of recurrent exposure to inhaled allergens, such as the epithelial changes seen in asthmatic patients. We developed a murine model in which chronic airway inflammation is maintained by repeated allergen [ovalbumin (OVA)] inhalation; using this model, we examined the response to mucosal administration of CpG DNA (oligonucleotides) and specific antigen immunotherapy. Mice repeatedly exposed to OVA developed significantly greater airway hyperresponsiveness and goblet cell hyperplasia, but not airway eosinophilia, compared with those exposed only twice. CpG-based immunotherapy significantly reversed both acute and chronic markers of inflammation as well as airway hyperresponsiveness. We further examined the effect of mucosal immunotherapy on the response to a second, unrelated antigen. Mice sensitized to both OVA and schistosome eggs, challenged with inhaled OVA, and then treated with OVA-directed immunotherapy demonstrated significant reduction of airway hyperresponsiveness and a moderate reduction in eosinophilia, after inhalation challenge with schistosome egg antigens. In this model, immunotherapy treatment reduced bronchoalveolar lavage (BAL) levels of Th2 cytokines (IL-4, IL-5, IL-13, and IL-10) without changing BAL IFN-gamma. Antigen recall responses of splenocytes from these mice demonstrated an antigen-specific (OVA) enhanced release of IL-10 from splenocytes of treated mice. These results suggest that CpG DNA may provide the basis for a novel form of immunotherapy of allergic asthma. Both antigen-specific and, to a lesser extent, antigen-nonspecific responses to mucosal administration of CpG DNA are seen.

Immunostimulatory Oligonucleotides Attenuate Airways Remodeling in Allergic Monkeys

“…Evaluations of the ability of CpG motifs to attenuate airways remodeling in mice have not been as complete. Both mucosal and systemic ISS have been reported to reduce/prevent mucous cell metaplasia in mice exposed to inhaled ovalbumin (8,9,28,29). However, this aspect of airways remodeling in mice does not accurately reflect the manifestation in humans.…”

“…ISS treatment (by systemic or mucosal delivery) has been shown to inhibit airways remodeling and airways hyperresponsiveness in murine models (5)(6)(7)(8)(9)(10). We have previously defined a nonhuman primate model of allergic asthma using aerosolized house dust mite allergen (HDMA) (Dermatophagoides farinae), a known human allergen (11).…”

Immunostimulatory CpG Oligonucleotides Abrogate Allergic Susceptibility in a Murine Model of Maternal Asthma Transmission

“…The main indicator of airflow obstruction, enhanced pause (Penh), which shows a strong correlation with the airway resistance examined by standard evaluation methods, was calculated from the box waveform (22). After measurement of baseline Penh, aerosolized PBS or methacholine (MCh-acetyl-␤-methylcholine chloride; Sigma-Aldrich) in increasing concentrations (6,12,25,50, and 100 mg/ml) was nebulized through an inlet of the chamber for 1 min, and Penh measurements were made for 9 min after each dose. Penh values for the first 2 min and the last 2 min after each nebulization were discarded, and the values for 5 min in between were averaged and used to compare results.…”

Intranasal CpG Therapy Attenuated Experimental Fungal Asthma in a TLR9-Dependent and -Independent Manner

“…Prophylactic, systemic CpG administration in acute allergic airway models driven by ovalbumin (OVA), Aspergillus antigen, or house dust mite elicits major protective effects [6,7,8]. Further, exogenously administered CpG has been shown to inhibit and/or reverse airway remodeling in an OVA model of allergic asthma even when administered after OVA challenge and establishment of airway disease [9,10,11]. The mechanism through which CpG inhibits or reverses allergic airway disease is attributed, in part, to the inhibition of Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13 and migration of Th2 cells into the lung environment [6,9,12,13,14].…”