title: Poly(anhydride) nanoparticles act as active Th1 adjuvants through Toll-like receptor exploitation.
abstract: The mechanisms that underlie the potent Th1-adjuvant capacity of poly(methyl vinyl ether-co-maleic anhydride) nanoparticles (NPs) were investigated. Traditionally, polymer NPs have been considered delivery systems that promote a closer interaction between antigen and antigen-presenting cells (APCs). Our results revealed that poly(anhydride) NPs also act as agonists of various Toll-like receptors (TLRs) (TLR2, -4, and -5), triggering a Th1-profile cytokine release (gamma interferon [IFN-gamma], 478 pg/ml versus 39.6 pg/ml from negative control; interleukin-12 [IL-12], 40 pg/ml versus 7.2 pg/ml from negative control) and, after incubation with dendritic cells, inducing a 2.5- to 3.5-fold increase of CD54 and CD86 costimulatory molecule expression. Furthermore, in vivo studies suggest that NPs actively elicit a CD8(+) T-cell response. Immunization with empty NPs resulted in a significant delay in the mean survival date (from day 7 until day 23 postchallenge) and a protection level of 30% after challenge against a lethal dose of Salmonella enterica serovar Enteritidis. Taken together, our results provide a better understanding of how NPs act as active Th1 adjuvants in immunoprophylaxis and immunotherapy through TLR exploitation.
authors.affiliation: Department of Microbiology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Tamayo
authors.forename: J M
authors.initials: JM
authors.lastname: Irache
authors.forename: C
authors.initials: C
authors.lastname: Mansilla
authors.forename: J
authors.initials: J
authors.lastname: Ochoa-Repáraz
authors.forename: J J
authors.initials: JJ
authors.lastname: Lasarte
authors.forename: C
authors.initials: C
authors.lastname: Gamazo
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D015870:Gene Expression; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D011095:Polyethylenes / Q000494:pharmacology*; D012477:Salmonella enteritidis / Q000276:immunology / Q000472:pathogenicity; D016019:Survival Analysis; D018417:Th1 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008298:Maleates; D011095:Polyethylenes; D051193:Toll-Like Receptors; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; C043105:poly(methyl vinyl ether-co-maleic anhydride)