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

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      Author(s)
      Gungor, B.
      Yagci, F. C.
      Tincer, G.
      Bayyurt, B.
      Alpdundar, E.
      Yildiz, S.
      Ozcan, M.
      Gursel, I.
      Gursel, M.
      Date
      2014
      Source Title
      Science Translational Medicine
      Print ISSN
      1946-6234
      Publisher
      American Association for the Advancement of Science
      Volume
      6
      Issue
      235
      Pages
      235 - 261
      Language
      English
      Type
      Article
      Item Usage Stats
      183
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      388
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      Abstract
      CpG 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.
      Keywords
      T-cells
      Spatiotemporal Regulation
      Antimicrobial Peptide
      Innate Immunity
      Tumor-antigen
      Mouth-disease
      I Interferons
      Self-dna
      B-cell
      Oligodeoxynucleotides
      Permalink
      http://hdl.handle.net/11693/12612
      Published Version (Please cite this version)
      http://dx.doi.org/10.1126/scitranslmed.3007909
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