CpG Oligodeoxynucleotide Inhibits Cockroach-Induced Asthma via Induction of IFN-γ⁺Th1 Cells or Foxp3⁺Regulatory T Cells in the Lung

Abstract

PurposeCpG oligodeoxynucleotide (CpG-ODN), a TLR9 agonist, activates innate immunity and induces Th1 response. Although the immune modulatory effect of CpG-ODN has been extensively studied, its function in cockroach extract-induced allergic asthma has not been studied. Here, we investigated the inhibitory function of CpG-ODN in cockroach extract-induced asthma in mice with different treatment schemes.MethodsScheme 1: BALB/C mice were intra-nasally co-administered by cockroach extract and CpG-ODN twice a week for 3 weeks; Scheme 2: The mice were intra-nasally pre-treated with CpG-ODN at day 0 and cockroach allergen challenge was performed from day 3 as in scheme 1. Scheme 3: Cockroach allergen challenge was performed as in scheme 1 and CpG-ODN was post-treated at day 21. Then, BAL cell count, flow cytometric analysis of alveolar macrophages, regulatory T cells, and lung tissue histology, Th1 and Th2 cytokines, serum IgE, cockroach specific IgE, IgG1/IgG2a ratio, and airway hyper-responsiveness were evaluated.ResultsMice with repeated intra-nasal exposure to CpG-ODN showed a dramatic decrease in eosinophilic inflammation, goblet cell hyperplasia, and airway hyper-responsiveness with reduction of IL-13, IL-5, and serum IgE, cockroach specific IgE and IgG1/IgG2a ratio. This inhibitory function might be related to the up-regulation of IL-10 and CD4+Foxp3+ regulatory T cells in the lung. Interestingly, one-time challenge of CpG-ODN either prior or posterior to cockroach extract exposure could modulate airway inflammation and hyper-responsiveness via increase of Th1 response.ConclusionsCollectively, our data suggest that CpG-ODN treatment modulates Th2 inflammation in the lung by induction of regulatory T cells or Th1 response in a cockroach-induced asthma model.

Dental follicle mesenchymal stem cells down‐regulate Th2‐mediated immune response in asthmatic patients mononuclear cells

“…In a recent study performed on murine model of asthma, it was shown that bone marrow‐derived mesenchymal stem cells reduced the production of IL‐4, IL‐5 and IL‐13 cytokine levels in mediastinal lymph nodes and slightly increased IFN‐γ levels . We observed that these results are compatible with previous studies, which demonstrated the inhibition of Th2 based inflammatory responses due to IFN‐γ production by Th1 cells . In addition, one of the studies on immunosuppressive activity of dental pulp MSCs on CD4 + T lymphocytes of healthy individuals it was reported that dental pulp MSCs decreased the frequency of Tbet and down‐regulated IFN‐γ expression of T lymphocytes by increasing FoxP3 expression and GATA3 expression was decreased in the cocultures .…”

TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract

“…In contrast, in B. tropicalis +CpG/Alum‐sensitized mice, the Th2 increase was not observed in WT or in IL‐10 –/– mice, indicating that IL‐10 is dispensable for CpG‐mediated inhibition of Th2 development. It should be noted that although CpG is known to increase Th1 or Treg activities, in our model, we could not detect an increase of Th1 or Treg cells. It is possible that during the B. tropicalis sensitization, dendritic cells receive a negative signal from endocytosed CpG that precludes the necessary signals required for effective Th2 sensitization.…”

Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells

“…Unmethylated CpG oligonucleotides (CpG‐ODN) sequences from bacterial DNA are TLR9 agonists that are able to activate B cells and plasmocytoid dendritic cells promote Th1 and Treg cells. Mouse models of allergic asthma demonstrated that CpG‐ODN alone or in combination with nanoparticles inhibits classical asthma features after allergen challenge . In humans, initial studies using the major allergen of ragweed pollen, Amb a 1, conjugated to CpGs demonstrated efficacy, but subsequent larger phase III clinical studies did not show significant differences between placebo and treated groups after 1 year .…”