Immunostimulatory activity of CpG oligonucleotides containing non-ionic methylphosphonate linkages.
Bacterial DNA and synthetic oligodeoxynucleotides containing unmethylated CpG-motifs in a particular sequence context activate vertebrate immune cells. We examined the significance of negatively charged internucleoside linkages in the flanking sequences 5' and 3' to the CpG-motif on immunostimulatory activity. Cell proliferation and secretion of IL-12 and IL-6 in mouse spleen cell cultures, and spleen weights of mice increased significantly when a non-ionic linkage was placed at least four or more internucleoside linkages away from the CpG-motif in the 5'-flanking sequence. When the non-ionic linkage was placed closer than three internucleoside linkages in the 5'-flanking sequence to the CpG-motif, immunostimulatory activity was suppressed compared with that observed with the unmodified parent oligo. In general, the placement of non-ionic linkage in the 3'-flanking sequence to the CpG-motif either did not affect or slightly increased immunostimulatory activity compared with the parent oligo. These results have significance in understanding CpG oligonucleotide-receptor interactions and the development of potent immunomodulatory agents.
Yu
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Hybridon Inc., 345 Vassar Street, Cambridge, MA 02139, USA.
Kandimalla
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ER
Zhao
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Cong
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Y
Agrawal
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D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018899:CpG Islands; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007111:Immunity, Cellular / Q000187:drug effects; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013163:Splenomegaly / Q000139:chemically induced; D013329:Structure-Activity Relationship
D000276:Adjuvants, Immunologic; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; C021992:dideoxyribonucleoside methylphosphonates; D018664:Interleukin-12