CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma☆☆☆★

Kline, Joel N.; Krieg, Arthur Μ.; Waldschmidt, Thomas J.; Ballas, Zuhair K.; Jain, Vipul V.; Businga, Thomas R.

doi:10.1016/s0091-6749(99)70022-9

Cited by 127 publications

(96 citation statements)

References 27 publications

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“…In this regard, Hansen et al demonstrated that adoptively transferred allergen-specific Th1 cells do not inhibit Th2-mediated airway hyperreactivity in mouse models of asthma [32]. Others have reported that CpG ODN can prevent allergic diseases even in mice genetically deficient in either or both Th1 and Th2 cytokines [33]. Likewise, in our present study, CpG ODN inhibited Th2 responses and eosinophil infiltration without manifesting an enhancement of the Th1 response at the local inflammatory site.…”

Section: Discussionsupporting

confidence: 63%

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model

et al. 2005

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The number of patients with severe atopic dermatitis (AD) has been on the rise recently. We are therefore urgently in need of a treatment that can suppress Th2 cell-mediated responses in an Ag-specific fashion. Oligodeoxynucleotides (ODN)containing CpG motifs (CpG ODN) have been highlighted as immunomodulators that reduce Th2-mediated responses. To determine the effect of CpG ODN on Th2-mediated skin inflammation, we first developed a reproducible murine model of protein Ag-induced eosinophilic inflammation that is accompanied by epidermal acanthosis and increased serum IgE levels as seen in AD. In this model we found that treatment with CpG ODN during epicutaneous sensitization in previously i.p.-primed mice prevented the development of Th2-mediated responses. Furthermore, to evaluate the therapeutic effect of CpG ODN on established eosinophilic inflammation, mice were treated with a course of the immunotherapy at a skin site remote from the area of Ag application prior to the second 1-wk epicutaneous exposure to Ag. Therapeutic treatment with CpG ODN plus Ag, but not that with CpG ODN alone, could reverse the established eosinophilic inflammation. The presented results provide strong evidence for the feasibility of a novel Ag-specific immunomodulator to treat cutaneous eosinophilic inflammation such as that characteristically found in patients with severe AD.

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Section: Discussionsupporting

confidence: 63%

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model

et al. 2005

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“…However, our findings differ from those of Kline et al (22), who reported that the anti-inflammatory effects of CpG ODN in the mouse model of asthma are independent of IL-12. In that report, CpG conferred protection against both airway eosinophilia and bronchial hyperreactivity in the absence of IFN-␥ or IL-12 or both IFN-␥ and IL-12 (22). It is possible that differences in the allergen model used (schistosome egg-Ag vs RW) to induce asthma or timing of CpG doses (during allergic sensitization in the Kline study and 48 h before RW challenge in sensitized mice in our study) may account for these differences.…”

Section: Discussionmentioning

confidence: 54%

In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Choudhury

Wild

Alam

et al. 2002

The Journal of Immunology

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DNA containing unmethylated CpG motifs is intrinsically immunostimulatory, inducing the production of a variety of cytokines and chemokines by immune cells. The strong Th1 response triggered by CpG oligodeoxynucleotide (ODN) inhibits the development of Th2-mediated allergic asthma in mice. This work documents that CpG ODN-induced IL-12 production plays a critical role in this process, because intrapulmonary CpG ODN inhibits allergic inflammation in wild-type but not IL-12−/− mice. CpG ODN rapidly localized to alveolar macrophages (AM), thereby triggering the phosphorylation of p38 mitogen-activated protein kinase (MAP kinase). AM cultured with CpG but not control ODN up-regulated IL-12 p40 expression and release, and these effects were blocked by the highly specific p38 MAP kinase inhibitor SB202190. Intrapulmonary administration of this inhibitor blocked the ability of CpG ODN to produce IL-12 in the lungs and reversed the anti-inflammatory effects of CpG ODN on allergic lung inflammation. These findings indicate that IL-12 production by AM is stimulated by intrapulmonary CpG ODN administration through a p38 MAP kinase-dependent process, and IL-12 is a key cytokine that mediates CpG ODN-induced protection against allergic lung inflammation.

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“…In animal models, triggering of TLR9 using CpGs has been shown to be effective against many features of allergic airway inflammatory responses (43)(44)(45)(46)(47)(48)(49)(50)(51). In recent mechanistic studies, this has been shown to be dependent on production of Th1 cytokines such as IFN-g and IL-12 (43), induction of regulatory factors including upregulation of IDO (47,48), and generation of Tregs (49), as well as functional impairment of APCs (50) and inhibition of DC migration (51).…”

Section: Discussionmentioning

confidence: 99%

“…In recent mechanistic studies, this has been shown to be dependent on production of Th1 cytokines such as IFN-g and IL-12 (43), induction of regulatory factors including upregulation of IDO (47,48), and generation of Tregs (49), as well as functional impairment of APCs (50) and inhibition of DC migration (51). In terms of the dependency on Th1 cytokine generation, it is still unresolved as to whether IFN-g or IL-12 is required for prevention of Th2 immune responses with CpG treatment (46). Many features of the mechanism of Th2 inhibition by CpG have been elucidated, but a unified theory has not been established.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of Inhibition of Allergic Immune Responses by a Novel Antedrug TLR7 Agonist

Matsui

Tomizawa

Eiho

et al. 2012

The Journal of Immunology

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Triggering innate immune responses through TLRs is expected to be a novel therapeutic strategy for the treatment of allergic diseases. TLR agonists are able to modulate Th2 immune responses through undefined mechanisms. We investigated the mechanism of action of the suppression of Th2 immune responses with a novel antedrug TLR7 agonist. The antedrug is rapidly metabolized by plasma esterases to an acid with reduced activity to limit systemic responses. Topical administration of this compound inhibited features of the allergic airway inflammatory response in rat and murine allergic airways model. Type I IFN played a role in the suppression of Th2 cytokines produced from murine splenocytes. Inhibition of Th2 immune responses with the antedrug TLR7 agonist was shown to be via a type I IFN–dependent mechanism following short-term exposure to the compound, although there might be type I IFN–independent mechanisms following long-term exposure. We have demonstrated that local type I IFN signaling and plasmacytoid dendritic cells, but not Th1 immune responses, are required for in vivo efficacy against murine airway Th2-driven eosinophilia. Furthermore, migration of dendritic cell subsets into the lung was related to efficacy and is dependent on type I IFN signaling. Thus, the mechanism of action at the cytokine and cellular level involved in the suppression of Th2 allergic responses has been characterized, providing a potential new approach to the treatment of allergic disease.

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CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic airway inflammation in a murine model of asthma☆☆☆★

Cited by 127 publications

References 27 publications

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model

Development of a novel Ag-specific immunotherapy using CpG oligodeoxynucleotides in a new, unique mouse cutaneous eosinophilic inflammation model

In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

Mechanism of Action of Inhibition of Allergic Immune Responses by a Novel Antedrug TLR7 Agonist

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