Impact of modifications of heterocyclic bases in CpG dinucleotides on their immune-modulatory activity

Journal of Leukocyte Biology
Jörg VollmerA M Krieg

Abstract

Synthetic phosphorothioate oligodeoxynucleotides (ODN) bearing unmethylated CpG motifs can mimic the immune-stimulatory effects of bacterial DNA and are recognized by Toll-like receptor 9 (TLR9). Past studies have demonstrated that nucleotide modifications at positions at or near the CpG dinucleotides can severely affect immune modulation. However, the effect of nucleotide modifications to stimulate human leukocytes and the mechanism by which chemically modified CpG ODN induce this stimulation are not well understood. We investigated the effects of CpG deoxyguanosine substitutions on the signaling mediated by human TLR9 transfected into nonresponsive cells. ODN incorporating most of these substitutions stimulated detectable TLR9-dependent signaling, but this was markedly weaker than that induced by an unmodified CpG ODN. One of the most active ODN tested contained deoxyinosine for deoxyguanosine substitutions (CpI ODN), but its relative activity to induce cytokine secretion on mouse cells was much weaker than on human cells. The activity was dependent on TLR9, as splenocytes from mice genetically deficient in TLR9 did not respond to CpI ODN stimulation. It is surprising that CpI ODN were nearly as strong as CpG ODN for inductio...Continue Reading

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Citations

Jun 7, 2005·Expert Opinion on Biological Therapy·Jörg Vollmer
Feb 13, 2009·Advanced Drug Delivery Reviews·Jörg Vollmer, Arthur M Krieg
Jan 10, 2008·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Susan L StevensMary P Stenzel-Poore
Oct 3, 2009·Annals of the New York Academy of Sciences·Denise Richardt-Pargmann, Jörg Vollmer
Nov 11, 2009·Journal of Receptor and Signal Transduction Research·Ryan J ArsenaultScott Napper
Nov 23, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhu GuoSuryaprakash Sambhara
Sep 1, 2019·International Journal of Molecular Sciences·Keiko YamakawaYoko Matsuda
Aug 7, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jiali LiRonald Levy

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