Immunostimulatory Oligonucleotides Attenuate Airways Remodeling in Allergic Monkeys

Fanucchi, Michelle V.; Schelegle, Edward S.; Baker, Gregory L.; Evans, Michael J.; McDonald, Ruth J.; Gershwin, Laurel J.; Hyde, Dallas M.; Plopper, Charles G.; Miller, Lisa

doi:10.1164/rccm.200404-533oc

Cited by 64 publications

(38 citation statements)

References 23 publications

(35 reference statements)

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“…In limited studies in mild asthmatics utilizing an allergen challenge study design, nebulized ISS did not reduce the number of sputum eosinophils or the late-phase response to allergen challenge [45] . Thus, further studies are needed to determine whether ISS, which has demonstrated therapeutic efficacy in mouse [19][20][21][22][23][24] and primate models of asthma [46] , is effective in humans with asthma.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor-9 Agonist Inhibits Airway Inflammation, Remodeling and Hyperreactivity in Mice Exposed to Chronic Environmental Tobacco Smoke and Allergen

Song

Min

Miller

et al. 2009

Int Arch Allergy Immunol

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er, and AHR. The reduced airway remodeling in mice treated with the TLR-9 agonist was associated with significantly reduced numbers of peribronchial MBP+ and peribronchial TGF-␤ 1 + cells, and with significantly reduced levels of lung Th2 cytokines [interleukin-5 and interleukin-13] and TGF-␤ 1 .Conclusion: These studies demonstrate that TLR-9-based therapies inhibit airway inflammation, remodeling and AHR in mice coexposed to ETS and allergen who exhibit enhanced airway inflammation and remodeling.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor-9 Agonist Inhibits Airway Inflammation, Remodeling and Hyperreactivity in Mice Exposed to Chronic Environmental Tobacco Smoke and Allergen

Song

Min

Miller

et al. 2009

Int Arch Allergy Immunol

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“…TLR9 agonists (i.e., ISS-ODN, also known as CpG-ODN) are potent inhibitors of experimental asthma in rodents (35)(36)(37) and primates (38). This inhibition is transient and lasts for 6 wk (39).…”

Section: Administration Of Iss-odn Prevents Th2 Phenotype Spreadmentioning

confidence: 99%

Induction and Inhibition of the Th2 Phenotype Spread: Implications for Childhood Asthma

Hayashi

Gong

Rossetto

et al. 2005

The Journal of Immunology

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The interactions between genetic and environmental factors play a major role in the development of childhood asthma. We hypothesized that a pre-existing Th2/asthmatic response can promote Th2 responses to newly encountered Ags (i.e., phenotype spread). To test this hypothesis, we developed a mouse model in which the requirements for the induction and inhibition of phenotype spread to a clinically relevant neo-allergen (i.e., ragweed) were investigated. Our results indicate that 1) phenotype spread to the neo-allergen can be induced only within the first 8 h after a bronchial challenge with the first Ag (OVA); 2) Th2 differentiation of naive CD4+ T cells occurs in bronchial lymph nodes; 3) trafficking of naive CD4+ T cells to local lymph nodes and IL-4 produced by OVA-activated Th2 cells play essential roles in the differentiation of naive CD4+ T cells to Th2 cells; and 4) suppression of the production of chemokines involved in the homing of naive CD4+ T and Th2 cells to bronchial lymph nodes by a TLR9 agonist inhibited phenotype spread and abrogated the consequent development of experimental asthma. These findings provide a mechanistic insight into Th2 phenotype spread and offer an animal model for testing relevant immunomodulatory interventions.

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“…ISS acutely inhibits Th2-mediated airway inflammation by inhibiting local lung antigen-presenting cell costimulatory molecule expression and by preventing Th2 cytokine release from airway Th2 cells, basophils, and/or mast cells, highlighting the functional importance of ISS delivery to the airways (9). ISS efficacy in mouse models of asthma has been subsequently confirmed in rhesus monkeys in which inhaled ISS suppresses airway hyperresponsiveness and cellular inflammation in the lung tissue (10). Importantly, recent clinical studies have demonstrated potential for ISS-allergen conjugate therapy in human allergic airways disease (11)(12)(13).…”

Section: Introductionmentioning

confidence: 97%

CpG-containing immunostimulatory DNA sequences elicit TNF-α–dependent toxicity in rodents but not in humans

Campbell¹,

Cho²,

Foster³

et al. 2009

J. Clin. Invest.

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CpG-containing immunostimulatory DNA sequences (ISS), which signal through TLR9, are being developed as a therapy for allergic indications and have proven to be safe and well tolerated in humans when administrated via the pulmonary route. In contrast, ISS inhalation has unexplained toxicity in rodents, which express TLR9 in monocyte/macrophage lineage cells as well as in plasmacytoid DCs (pDCs) and B cells, the principal TLR9-expressing cells in humans. We therefore investigated the mechanisms underlying this rodent-specific toxicity and its implications for humans. Mice responded to intranasally administered 1018 ISS, a representative B class ISS, with strictly TLR9-dependent toxicity, including lung inflammation and weight loss, that was fully reversible and pDC and B cell independent. Knockout mouse experiments demonstrated that ISSinduced toxicity was critically dependent on TNF-α, with IFN-α required for TNF-α induction. In contrast, human PBMCs, human alveolar macrophages, and airway-derived cells from Ascaris suum-allergic cynomolgus monkeys did not produce appreciable TNF-α in vitro in response to ISS stimulation. Moreover, sputum of allergic humans exposed to inhaled ISS demonstrated induction of IFN-inducible genes but minimal TNF-α induction. These data demonstrate that ISS induce rodent-specific TNF-α-dependent toxicity that is absent in humans and reflective of differential TLR9 expression patterns in rodents versus humans.

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Immunostimulatory Oligonucleotides Attenuate Airways Remodeling in Allergic Monkeys

Cited by 64 publications

References 23 publications

Toll-Like Receptor-9 Agonist Inhibits Airway Inflammation, Remodeling and Hyperreactivity in Mice Exposed to Chronic Environmental Tobacco Smoke and Allergen

Toll-Like Receptor-9 Agonist Inhibits Airway Inflammation, Remodeling and Hyperreactivity in Mice Exposed to Chronic Environmental Tobacco Smoke and Allergen

Induction and Inhibition of the Th2 Phenotype Spread: Implications for Childhood Asthma

CpG-containing immunostimulatory DNA sequences elicit TNF-α–dependent toxicity in rodents but not in humans

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