Superior activity of the type C class of ISS in vitro and in vivo across multiple species

DNA Cell Biol. 2005 Feb;24(2):63-72. doi: 10.1089/dna.2005.24.63.

Abstract

CpG-C are a novel class of CpG motif-containing immunostimulatory sequences (ISS) that includes both a 5'-TCG element and a CpG-containing palindrome. CpG-C drive all known ISS activities and, in particular, are potent enhancers of IFN-alpha from plasmacytoid dendritic cells (PDCs). In our examination of CpG-C sequence requirements, we determined that optimal IFN-alpha-inducing activity could be achieved with longer palindromes. Longer palindromes also correlated with maintenance of the double-stranded (ds) form despite concentration and pH changes, indicating a preference for ds oligodeoxynucleotides (ODNs) by the ISS-induced signaling mechanism for IFN-alpha synthesis. This correlation did not hold for all arms of the ISS-induced immune response, since we did not observe increased B cell activity with the longer palindrome CpG-C ODNs. We further demonstrated that CpG-C retained activity in an in vitro primate system and induced the expression of several cytokines and IFN-alpha-inducible genes when CpG-C were administered in vivo to mice and primates. In conclusion, we have shown CpG-C to exert several types of immune functions across multiple species, and this novel class is thus an attractive candidate for ISS-based therapeutic strategies.

MeSH terms

  • Adjuvants, Immunologic / genetics
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • Cell Proliferation
  • CpG Islands / genetics
  • Cytokines / biosynthesis*
  • Female
  • GTP-Binding Proteins / biosynthesis
  • GTP-Binding Proteins / genetics
  • Gene Expression / drug effects*
  • Gene Expression / physiology
  • Gene Expression Regulation / physiology
  • Humans
  • Interferon-alpha / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism
  • Lymph Nodes / chemistry
  • Lymph Nodes / metabolism
  • Mice
  • Myxovirus Resistance Proteins
  • Oligodeoxyribonucleotides / genetics
  • Oligodeoxyribonucleotides / pharmacology*
  • Papio
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics

Substances

  • Adjuvants, Immunologic
  • C792 oligodeoxynucleotide
  • CPG-oligonucleotide
  • Cytokines
  • IFIT2 protein, human
  • Interferon-alpha
  • Interleukin-6
  • Myxovirus Resistance Proteins
  • Oligodeoxyribonucleotides
  • RNA, Messenger
  • Transcription Factors
  • Interleukin-12
  • Interferon-gamma
  • GTP-Binding Proteins