title: The induction of innate and adaptive immunity by biodegradable poly(γ-glutamic acid) nanoparticles via a TLR4 and MyD88 signaling pathway.
abstract: The induction of adaptive immunity through the activation of innate immunity is indispensable for vaccine development. Although strategies for particulate antigen delivery are widely investigated, their immunological mechanisms are unclear. We describe in this study that biodegradable nanoparticles (NPs) elaborated with poly(γ-glutamic acid) (γ-PGA) are able to induce potent innate and adaptive immune responses through Toll-like receptor 4 (TLR4) and MyD88 signaling pathways. The production of inflammatory cytokines from macrophages and the maturation of dendritic cells were impaired in MyD88-knockout and TLR4-deficient mice compared with their wild-types, when the cells were stimulated with γ-PGA NPs. The immunization of these mice with antigen-carrying γ-PGA NPs also resulted in diminished induction of antigen-specific cellular immune responses. These results suggest that γ-PGA NPs have not only an antigen-carrying capacity but also a potent adjuvant function of eliciting adaptive immune responses to the carrying antigen through recognition of the first-line host-sensor system.
authors.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Uto
authors.forename: Takami
authors.initials: T
authors.lastname: Akagi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toyama
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Akashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D007113:Immunity, Innate / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008422:Materials Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D053758:Nanoparticles / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D001672:Biocompatible Materials; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D011112:Polymyxin B