title: Robust stimulation of humoral and cellular immune responses following vaccination with antigen-loaded beta-glucan particles.
abstract: beta-Glucan particles (GPs) are purified Saccharomyces cerevisiae cell walls treated so that they are primarily beta1,3-d-glucans and free of mannans and proteins. GPs are phagocytosed by dendritic cells (DCs) via the Dectin-1 receptor, and this interaction stimulates proinflammatory cytokine secretion by DCs. As the hollow, porous GP structure allows for high antigen loading, we hypothesized that antigen-loaded GPs could be exploited as a receptor-targeted vaccine delivery system. Ovalbumin (OVA) was electrostatically complexed inside the hollow GP shells (GP-OVA). Incubation of C57BL/6J mouse bone marrow-derived DCs with GP-OVA resulted in phagocytosis, upregulation of maturation markers, and rapid proteolysis of OVA. Compared with free OVA, GP-OVA was >100-fold more potent at stimulating the proliferation of OVA-reactive transgenic CD8(+) OT-I and CD4(+) OT-II T cells, as measured by in vitro [(3)H]thymidine incorporation using DCs as antigen-presenting cells. Next, immune responses in C57BL/6J mice following subcutaneous immunizations with GP-OVA were compared with those in C57BL/6J mice following subcutaneous immunizations with OVA absorbed onto the adjuvant alum (Alum/OVA). Vaccination with GP-OVA stimulated substantially higher antigen-specific CD4(+) T-cell lymphoproliferative and enzyme-linked immunospot (ELISPOT) responses than that with Alum/OVA. Moreover, the T-cell responses induced by GP-OVA were Th1 biased (determined by gamma interferon [IFN-gamma] ELISPOT assay) and Th17 biased (determined by interleukin-17a [IL-17a] ELISPOT assay). Finally, both the GP-OVA and Alum/OVA formulations induced strong secretions of IgG1 subclass anti-OVA antibodies, although only GP-OVA induced secretion of Th1-associated IgG2c antibodies. Thus, the GP-based vaccine platform combines adjuvanticity and antigen delivery to induce strong humoral and Th1- and Th17-biased CD4(+) T-cell responses.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Huang
authors.forename: Gary R
authors.initials: GR
authors.lastname: Ostroff
authors.forename: Chrono K
authors.initials: CK
authors.lastname: Lee
authors.forename: Charles A
authors.initials: CA
authors.lastname: Specht
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Levitz
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism; D014611:Vaccination; D047071:beta-Glucans / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D047071:beta-Glucans; D010047:Ovalbumin
references.citation: Infect Immun. 2008 Oct;76(10):4764-71
references.pmid: 18678670
references.citation: J Immunol. 2009 Jun 15;182(12):7587-94
references.pmid: 19494282
references.citation: Am J Pathol. 2009 Dec;175(6):2489-500
references.pmid: 19893050
references.citation: Immunol Rev. 2004 Jun;199:9-26
references.pmid: 15233723
references.citation: Nature. 2009 Apr 30;458(7242):1180-4
references.pmid: 19407801
references.citation: Bioessays. 2006 Aug;28(8):799-808
references.pmid: 16927300
references.citation: Int J Immunopharmacol. 1988;10(4):405-14
references.pmid: 3262594
references.citation: Nat Med. 2008 Mar;14(3):258-65
references.pmid: 18311150
references.citation: J Immunol. 2006 Aug 15;177(4):2276-84
references.pmid: 16887988
references.citation: J Infect Dis. 2004 Aug 1;190(3):624-31
references.pmid: 15243941
references.citation: Cell Host Microbe. 2009 Apr 23;5(4):311-3
references.pmid: 19380108
references.citation: J Exp Clin Cancer Res. 2008 Sep 19;27:40
references.pmid: 18803849
references.citation: Vaccine. 2009 Nov 23;27(50):7116-24
references.pmid: 19786146
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4612-21
references.pmid: 19584156
references.citation: Immunol Rev. 2007 Oct;219:143-56
references.pmid: 17850487
references.citation: Cell Host Microbe. 2009 Apr 23;5(4):329-40
references.pmid: 19380112
references.citation: Science. 2007 Jan 5;315(5808):107-11
references.pmid: 17204652
references.citation: Eur J Immunol. 2009 May;39(5):1379-86
references.pmid: 19291703
references.citation: J Immunol Methods. 1999 Feb 1;223(1):77-92
references.pmid: 10037236
references.citation: J Immunol Methods. 1998 Mar 15;212(2):187-92
references.pmid: 9672206
references.citation: Nat Rev Immunol. 2009 Jul;9(7):465-79
references.pmid: 19521399
references.citation: Ann N Y Acad Sci. 2008 Nov;1143:45-60
references.pmid: 19076344
references.citation: Curr Opin Immunol. 2006 Feb;18(1):85-91
references.pmid: 16326087
references.citation: J Infect Dis. 1999 Dec;180(6):1957-68
references.pmid: 10558953
references.citation: Immunol Rev. 2005 Oct;207:166-83
references.pmid: 16181335
references.citation: Nature. 2006 Apr 6;440(7085):808-12
references.pmid: 16489357
references.citation: J Immunol. 1985 Nov;135(5):3388-93
references.pmid: 4045195
references.citation: J Immunol. 2002 Oct 1;169(7):3876-82
references.pmid: 12244185
references.citation: Blood. 2008 Dec 15;112(13):4971-80
references.pmid: 18818389
references.citation: Infect Immun. 2009 May;77(5):1774-81
references.pmid: 19273561
references.citation: PLoS One. 2008 Feb 27;3(2):e1691
references.pmid: 18301768
references.citation: Nat Immunol. 2007 Jun;8(6):549-51
references.pmid: 17514204
references.citation: J Immunol. 2004 Jul 15;173(2):797-806
references.pmid: 15240666
references.citation: Nat Immunol. 2007 Jun;8(6):630-8
references.pmid: 17450144
references.citation: Methods Mol Biol. 2010;605:177-88
references.pmid: 20072881
references.citation: Bioconjug Chem. 2008 Apr;19(4):840-8
references.pmid: 18376856
references.citation: Nat Immunol. 2010 Jan;11(1):83-9
references.pmid: 19935657
references.citation: Infect Immun. 1982 Mar;35(3):947-51
references.pmid: 7068224
references.citation: Nature. 2001 Sep 6;413(6851):36-7
references.pmid: 11544516
references.citation: Trends Immunol. 2007 May;28(5):227-33
references.pmid: 17403614
references.citation: Nature. 2007 Sep 27;449(7161):419-26
references.pmid: 17898760
references.citation: J Control Release. 2010 Jun 1;144(2):118-26
references.pmid: 20156497
references.citation: J Immunotoxicol. 2008 Jan;5(1):47-57
references.pmid: 18382858
references.citation: Nat Immunol. 2007 Jun;8(6):639-46
references.pmid: 17486092