Treatment of established asthma in a murine model using CpG oligodeoxynucleotides

Abstract

Allergen immunotherapy is an effective but underutilized treatment for atopic asthma. We have previously demonstrated that CpG oligodeoxynucleotides (CpG ODN) can prevent the development of a murine model of asthma. In the current study, we evaluated the role of CpG ODN in the treatment of established eosinophilic airway inflammation and bronchial hyperreactivity in a murine model of asthma. In this model, mice with established ovalbumin (OVA)-induced airway disease were given a course of immunotherapy (using low doses of OVA) in the presence or absence of CpG ODN. All mice then were rechallenged with experimental allergen. Untreated mice developed marked airway eosinophilia and bronchial hyperresponsiveness, which were significantly reduced by treatment with OVA and CpG. CpG ODN leads to induction of antigen-induced Th1 cytokine responses; successful therapy was associated with induction of the chemokines interferon-␥-inducible protein-10 and RANTES and suppression of eotaxin. Unlike previous studies, these data demonstrate that the combination of CpG ODN and allergen can effectively reverse established atopic eosinophilic airway disease, at least partially through redirecting a Th2 to a Th1 response. allergy; cytokines; Th1/Th2; lung; immunomodulators ONCE CONSIDERED A DISEASE of bronchospasm, asthma is now recognized to be an inflammatory disorder of the airways, which is associated with bronchial hyperreactivity and bronchospasm. The expression and release of T helper (Th) 2-like cytokines, frequently prompted by response to allergen, promote this inflammatory response. These cytokines, notably interleukin (IL)-4, IL-5, and IL-13, induce eosinophil chemotaxis and activation, mast cell stimulation, and IgE production in atopic as well as in nonatopic asthma. Although the molecular mechanisms of inflammation are similar in both types of asthma, the role of the antigen in inducing these inflammatory responses is central in atopic asthma. Moreover, although not all atopic individuals develop asthma, atopy is the single most important predictor for the development of asthma. Thus prevention and reversal of allergen-induced inflammation could have a significant impact on the morbidity of asthma.

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

“…10B). Instead, in these mice, there was a tendency for lower cytokine levels, including IL-5 and IL-13 in Bbs2 Ϫ/Ϫ ; these cytokines are often increased in this model and in clinical asthma (29,30). These results suggest that loss of BBS2 or BBS4 did not predispose mice to increased asthma-like responses.…”

“…As an additional assessment, we measured cells and cytokine levels in bronchoalveolar lavage liquid after ovalbumin challenge (29). The total and differential cell counts did not differ in wild-type and Bbs Ϫ/Ϫ mice (SI Fig.…”

“…Mice were then challenged with inhaled OVA (1% solution, 30 min) on days 14 and 16. Airway hyperresponsiveness to inhaled methacholine was measured by using whole-body plethysmography as described (29). Responses were measured by using the enhanced pause (Penh).…”

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

“…3 For example, TLR9 activation by hypomethylated CpG oligodeoxynucleotides or CpG shifts immune responses away from Th2-type toward Th1-type immune responses 4 ; this shift at least partially contributes to the inhibitory effect of CpG in experimental allergic asthma models. [5][6][7][8] Unlike the findings in experimental models, promoting TLR9 activation with CpG has had limited therapeutic success in clinical asthma. 9 An explanation for the disparity between CpG effects in experimental and clinical disease presumably involves multiple factors, such as species differences in the cellular distribution of TLR9 10 and differential effects of mouseversus human-specific CpG.…”

Impaired Lung Dendritic Cell Migration and T Cell Stimulation Induced by Immunostimulatory Oligonucleotides Contribute to Reduced Allergic Airway Inflammation

“…CpG has been shown to reduce key features of allergic asthma and airway inflammation, such as airway hyperresponsiveness, mucus production, and airway eosinophil infiltration in mouse models (9 -16). CpG was effective when given before allergen challenge (11,13,14) and has even been demonstrated to reverse established disease (12,17,18). Given that CpG activates the innate immune system, thereby inducing release of cytokines to generate Th1 cells, such as TNF-␣, IL-12, IFN-␣, and indirectly, IFN-␥ (7,8), it was postulated that longterm treatment with CpG would lead to a rebalancing of Th1/Th2 responses (19).…”