title: A liquid crystal of ascorbyl palmitate, used as vaccine platform, provides sustained release of antigen and has intrinsic pro-inflammatory and adjuvant activities which are dependent on MyD88 adaptor protein.
abstract: Modern subunit vaccines require the development of new adjuvant strategies. Recently, we showed that CpG-ODN formulated with a liquid crystal nanostructure formed by self-assembly of 6-O-ascorbyl palmitate (Coa-ASC16) is an attractive system for promoting an antigen-specific immune response to weak antigens. Here, we showed that after subcutaneous injection of mice with near-infrared fluorescent dye-labeled OVA antigen formulated with Coa-ASC16, the dye-OVA was retained at the injection site for a longer period than when soluble dye-OVA was administered. Coa-ASC16 alone elicited a local inflammation, but how this material triggers this response has not been described yet. Although it is known that some materials used as a platform are not immunologically inert, very few studies have directly focused on this topic. In this study, we explored the underlying mechanisms concerning the interaction between Coa-ASC16 and the immune system and we found that the whole inflammatory response elicited by Coa-ASC16 (leukocyte recruitment and IL-1β, IL-6 and IL-12 production) was dependent on the MyD88 protein. TLR2, TLR4, TLR7 and NLRP3-inflammasome signaling were not required for induction of this inflammatory response. Coa-ASC16 induced local release of self-DNA, and in TLR9-deficient mice IL-6 production was absent. In addition, Coa-ASC16 revealed an intrinsic adjuvant activity which was affected by MyD88 and IL-6 absence. Taken together these results indicate that Coa-ASC16 used as a vaccine platform is effective due to the combination of the controlled release of antigen and its intrinsic pro-inflammatory activity. Understanding how Coa-ASC16 works might have significant implications for rational vaccine design.
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: María F
authors.initials: MF
authors.lastname: Sánchez Vallecillo
authors.affiliation: Departamento de Inmunología y Oncología, CNB (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: María M
authors.initials: MM
authors.lastname: Minguito de la Escalera
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: María V
authors.initials: MV
authors.lastname: Aguirre
authors.affiliation: Departamento de Farmacia, UNITEFA (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Gabriela V
authors.initials: GV
authors.lastname: Ullio Gamboa
authors.affiliation: Departamento de Farmacia, UNITEFA (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Santiago D
authors.initials: SD
authors.lastname: Palma
authors.affiliation: Departamento de Inmunología y Oncología, CNB (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: González-Cintado
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Chiodetti
authors.affiliation: Departamento de Matemática y Física, INFIQC (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Germán
authors.initials: G
authors.lastname: Soldano
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Morón
authors.affiliation: Departamento de Farmacia, UNITEFA (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Allemandi
authors.affiliation: Departamento de Inmunología y Oncología, CNB (CSIC), Darwin 3, 28049 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ardavín
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Pistoresi-Palencia
authors.affiliation: Departamento de Bioquímica Clínica, CIBICI (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina. Electronic address: belkys@fcq.unc.edu.ar.
authors.forename: Belkys A
authors.initials: BA
authors.lastname: Maletto
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D003692:Delayed-Action Preparations; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis; D007962:Leukocytes / Q000187:drug effects; D050866:Liquid Crystals; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics; D051193:Toll-Like Receptors / Q000096:biosynthesis; D014612:Vaccines / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D003692:Delayed-Action Preparations; D058847:Inflammasomes; D007378:Interleukins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014612:Vaccines; D010047:Ovalbumin; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid
keywords: Ascorbyl palmitate; Controlled release; Danger-associated molecular patterns (DAMPs); Liquid crystal; Nanostructure; Vaccine adjuvant