title: Mechanism of action of inhibition of allergic immune responses by a novel antedrug TLR7 agonist.
abstract: 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.
authors.affiliation: Pharmacology Research Laboratory, Dainippon Sumitomo Pharma Co., Ltd., Osaka 541-0045, Japan. hiroyuki-matsui@ds-pharma.co.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsui
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomizawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Eiho
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kashiwazaki
authors.forename: Susan
authors.initials: S
authors.lastname: Edwards
authors.forename: Mark
authors.initials: M
authors.lastname: Biffen
authors.forename: John P
authors.initials: JP
authors.lastname: Bell
authors.forename: Ashwani
authors.initials: A
authors.lastname: Bahl
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Leishman
authors.forename: Clare M
authors.initials: CM
authors.lastname: Murray
authors.forename: Haruo
authors.initials: H
authors.lastname: Takaku
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004802:Eosinophilia / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007370:Interferon Type I; D011355:Prodrugs; D051199:Toll-Like Receptor 7