title: Modifications incorporated in CpG motifs of oligodeoxynucleotides lead to antagonist activity of toll-like receptors 7 and 9.
abstract: Oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotides act as agonists of TLR9 and induce Th1-type immune responses. In the present study, we synthesized CpG containing ODNs in which C or G was substituted with 2'-O-methylribonucleotides, 5-methyl-dC, or 2'-O-methyl-5-methyl-C and studied their immune stimulatory activity alone and in combination with TLR agonists. In mouse and human primary cell-based assays, modified ODNs did not stimulate immune responses but inhibited TLR9 agonist-induced immune stimulatory activity. In mice, modified ODNs did not induce cytokines but inhibited immune responses induced by agonists of TLR7 and TLR9. Modified ODNs did not inhibit endosomal TLR3- or cell-surface TLR4-agonist-induced cytokines. This study demonstrates that ODNs incorporated with chemical modifications in CpG dinucleotides do not induce immune stimulatory activity but act as antagonists of TLR7 and TLR9 in vitro and in vivo. These types of modifications are commonly employed in antisense sequences and thereby may affect the intended mechanism of action.
authors: Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, MA 02139, USA.
authors: Dong
authors: D
authors: Yu
authors: Daqing
authors: D
authors: Wang
authors: Fu-Gang
authors: FG
authors: Zhu
authors: Lakshmi
authors: L
authors: Bhagat
authors: Meiru
authors: M
authors: Dai
authors: Ekambar R
authors: ER
authors: Kandimalla
authors: Sudhir
authors: S
authors: Agrawal
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000037:antagonists & inhibitors*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection
chemical_list: D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D018664:Interleukin-12