title: The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant.
abstract: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent type I interferon (IFN) inducer, was evaluated as a chemotherapeutic agent in mouse cancer models and proved to be well tolerated in human cancer clinical trials. Despite its multiple biological functions, DMXAA has not been fully characterized for the potential application as a vaccine adjuvant. In this report, we show that DMXAA does act as an adjuvant due to its unique property as a soluble innate immune activator. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. The adjuvant effect was directly dependent on the IRF3-mediated production of type-I-interferon, but not IL-33. DMXAA could also enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. We propose that DMXAA can be used as an adjuvant that targets a specific innate immune signaling pathway via IRF3 for potential applications including vaccines against influenza which requires a high safety profile.
authors.affiliation: Singapore Immunology Network, Agency for Science and Technology Research, Singapore.
authors.forename: Choon Kit
authors.initials: CK
authors.lastname: Tang
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.forename: Nao
authors.initials: N
authors.lastname: Jounai
authors.forename: Junichi
authors.initials: J
authors.lastname: Ito
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohata
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Dessailly
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D044004:Xanthones / Q000627:therapeutic use*
chemical_list: D000276:Adjuvants, Immunologic; C506535:Il33 protein, mouse; D050838:Interferon Regulatory Factor-3; D000067596:Interleukin-33; D007378:Interleukins; D044004:Xanthones; C066668:vadimezan
references.citation: J Clin Oncol. 2011 Aug 1;29(22):2965-71
references.pmid: 21709202
references.citation: Nat Rev Immunol. 2012 Jun 22;12(7):479-91
references.pmid: 22728526
references.citation: Nat Med. 2011 Jul 17;17(8):996-1002
references.pmid: 21765404
references.citation: J Leukoc Biol. 2011 Mar;89(3):351-7
references.pmid: 21084628
references.citation: J Biomed Sci. 2011 Mar 08;18:21
references.pmid: 21385449
references.citation: Mol Immunol. 2002 Dec;39(9):531-6
references.pmid: 12431386
references.citation: Neoplasia. 2010 Sep;12(9):755-65
references.pmid: 20824052
references.citation: Cell Host Microbe. 2010 Jan 21;7(1):50-61
references.pmid: 20114028
references.citation: J Immunol. 2008 May 15;180(10):6885-91
references.pmid: 18453609
references.citation: J Immunol. 2002 Jul 1;169(1):375-83
references.pmid: 12077267
references.citation: J Biol Chem. 2012 Nov 16;287(47):39776-88
references.pmid: 23027866
references.citation: J Exp Med. 2007 Jul 9;204(7):1559-69
references.pmid: 17562815
references.citation: Sci Transl Med. 2010 Mar 31;2(25):25ra24
references.pmid: 20424013
references.citation: Biochem Pharmacol. 2011 Nov 1;82(9):1175-85
references.pmid: 21819972
references.citation: J Biol Chem. 2010 Apr 2;285(14):10553-62
references.pmid: 20118240
references.citation: J Immunol. 2005 Mar 1;174(5):2720-9
references.pmid: 15728480
references.citation: Br J Cancer. 2008 Dec 16;99(12):2006-12
references.pmid: 19078952
references.citation: Br J Cancer. 1995 Jun;71(6):1204-9
references.pmid: 7779712
references.citation: Nature. 2009 Oct 8;461(7265):788-92
references.pmid: 19776740
references.citation: Nat Immunol. 2006 Jan;7(1):40-8
references.pmid: 16286919
references.citation: Am J Respir Cell Mol Biol. 2011 Sep;45(3):480-8
references.pmid: 21148741
references.citation: Nature. 2008 Oct 2;455(7213):674-8
references.pmid: 18724357
references.citation: Int J Cancer. 2005 Aug 20;116(2):322-6
references.pmid: 15800918
references.citation: Cancer Res. 2007 Jul 15;67(14):7011-9
references.pmid: 17638914
references.citation: Nature. 2011 Sep 25;478(7370):515-8
references.pmid: 21947006
references.citation: Immunity. 2005 Nov;23(5):479-90
references.pmid: 16286016
references.citation: Br J Cancer. 2004 Feb 23;90(4):906-10
references.pmid: 14970872
references.citation: Biomaterials. 2009 Mar;30(7):1389-400
references.pmid: 19058846
references.citation: J Immunol. 2012 Jul 1;189(1):50-60
references.pmid: 22634618
references.citation: Immunity. 2010 Nov 24;33(5):765-76
references.pmid: 21074459