CpG ODN Nanorings Induce IFNa from Plasmacytoid Dendritic Cells and Demonstrate Potent Vaccine Adjuvant Activity

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dc.citation.epage261en_US
dc.citation.issueNumber235en_US
dc.citation.spage235en_US
dc.citation.volumeNumber6en_US
dc.contributor.authorGungor, B.en_US
dc.contributor.authorYagci, F. C.en_US
dc.contributor.authorTincer, G.en_US
dc.contributor.authorBayyurt, B.en_US
dc.contributor.authorAlpdundar, E.en_US
dc.contributor.authorYildiz, S.en_US
dc.contributor.authorOzcan, M.en_US
dc.contributor.authorGursel, I.en_US
dc.contributor.authorGursel, M.en_US
dc.date.accessioned2015-07-28T12:02:11Z
dc.date.available2015-07-28T12:02:11Z
dc.date.issued2014en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractCpG oligodeoxynucleotides (ODN) are short single-stranded synthetic DNA molecules that activate the immune system and have been found to be effective for preventing and treating infectious diseases, allergies, and cancers. Structurally distinct classes of synthetic ODN expressing CpG motifs differentially activate human immune cells. K-type ODN (K-ODN), which have progressed into human clinical trials as vaccine adjuvants and immunotherapeutic agents, are strong activators of B cells and trigger plasmacytoid dendritic cells (pDCs) to differentiate and produce tumor necrosis factor-alpha (TNF alpha). In contrast, D-type ODN (D-ODN) stimulate large amounts of interferon-alpha (IFN alpha) secretion from pDCs. This activity depends on the ability of D-ODN to adopt nanometer-sized G quadruplex-based structures, complicating their manufacturing and hampering their progress into the clinic. In search of a D-ODN substitute, we attempted to multimerize K-ODN into stable nanostructures using cationic peptides. We show that short ODN with a rigid secondary structure form nuclease-resistant nanorings after condensation with the HIV-derived peptide Tat((47-57)). The nanorings enhanced cellular internalization, targeted the ODN to early endosomes, and induced a robust IFN alpha response from human pDCs. Compared to the conventional K-ODN, nanorings boosted T helper 1-mediated immune responses in mice immunized with the inactivated foot and mouth disease virus vaccine and generated superior antitumor immunity when used as a therapeutic tumor vaccine adjuvant in C57BL/6 mice bearing ovalbumin-expressing EG.7 thymoma tumors. These results suggest that the nanorings can act as D-ODN surrogates and may find a niche for further clinical applications.en_US
dc.identifier.doi10.1126/scitranslmed.3007909en_US
dc.identifier.issn1946-6234
dc.identifier.urihttp://hdl.handle.net/11693/12612
dc.language.isoEnglishen_US
dc.publisherAmerican Association for the Advancement of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1126/scitranslmed.3007909en_US
dc.source.titleScience Translational Medicineen_US
dc.subjectT-cellsen_US
dc.subjectSpatiotemporal Regulationen_US
dc.subjectAntimicrobial Peptideen_US
dc.subjectInnate Immunityen_US
dc.subjectTumor-antigenen_US
dc.subjectMouth-diseaseen_US
dc.subjectI Interferonsen_US
dc.subjectSelf-dnaen_US
dc.subjectB-cellen_US
dc.subjectOligodeoxynucleotidesen_US
dc.titleCpG ODN Nanorings Induce IFNa from Plasmacytoid Dendritic Cells and Demonstrate Potent Vaccine Adjuvant Activityen_US
dc.typeArticleen_US

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