Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction

Abstract

A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)–mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c+APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E–dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.

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

“…In contrast to our findings, Hessel et al (19) described a drastic reduction in the overall expression of costimulatory molecules on CD11c ϩ DC from the airways of CpG-treated mice, including PD-L1, PD-L2, CD40, ICOS, CD80, and CD86, accompanied by a clear reduction in the expression of MHC class II molecules, creating an overall picture of a much less competent DC. We speculate that these differences as compared with our observations may result from different isolation protocols for lung DC, and that the studies by Hessel et al (19) studied cytokine production of Th2 cells instead of T cell proliferation.…”

“…Studies investigating these immediate effects demonstrated that the impact of CpG on allergen-induced eosinophil infiltration is partially dependent on IFN-␥ (12,20), whereas others provide evidence that cytokines, such as IL-12 or IFN-␥, are of minor importance (21)(22)(23)(24). More recently, a study showed that CpG inhibits the Th2 response by rendering lung APCs unable to effectively present Ag to Th2 cells, but not to Th1 cells (19). In addition, CpG inhibited the IgE-dependent release of Th2 cytokines, especially IL-4, from basophils and/or mast cells in the airways of Th2-primed mice.…”

“…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). This, however, would not explain the immediate inhibitory effects of CpG on allergen-induced Th2 response.…”

An Anti-Inflammatory Role for Plasmacytoid Dendritic Cells in Allergic Airway Inflammation

“…In our experiments, the instillation of CpG motifs strongly reduced airway inflammation, similar to previous reports (29 -31). The explanation for this effect has been the inhibition of both Th2 cell activation and IgE-mediated cytokine induction (32) and the induction of IDO in the epithelial layer of the lungs (58). Here, we show not only that the effect induced by CpG motifs was partially mediated by pDCs, but also that the degree of maturation of these pDCs did not seem to influence their suppressive effect.…”

Treatment with the TLR7 agonist R848 induces regulatory T‐cell‐mediated suppression of established asthma symptoms

“…Mouse models of allergic asthma have long been used to dissect the immunological mechanisms leading to asthma, and despite the heterogeneity of experimental protocols in terms of strain differences, type and dose of antigen, time and route of administration, most studies have provided evidence for protective effects of natural or synthetic TLR2, TLR4, or TLR9 ligands in allergen-induced lung inflammation [1][2][3][4][5]. Similarly, the synthetic ligand of TLR7, R848 (or resiquimod), has been reported to prevent typical respiratory syndromes (airway hyperresponsiveness) and allergic inflammation (recruitment of eosinophils to the lung, production of IgE Abs, and Th2-driven cytokine production) [5][6][7][8] in treated mice.…”