Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9.
Oligodeoxyribonucleotides containing unmethylated CpG motifs act as TLR9 agonists. In this study, we evaluated oligonucleotides containing an unmethylated CpG motif in which two nucleotides adjacent to the CpG dinucleotide were substituted with 2'-O-methylribonucleotides, resulting in TLR7 and TLR9 antagonists. In mouse and human cell cultures, antagonists did not stimulate immune activation but inhibited TLR7 and TLR9 agonist-induced activity. In mice, antagonists inhibited immune responses induced by TLR9 agonists for up to several days, and the inhibition was dose-dependent. Antagonists also inhibited immune responses induced by an RNA-based TLR7/8 agonist but not TLRs 2, 3, 4, or 5 agonists in mice. Additionally, antagonist inhibited TLR9 agonist-induced IL-6 in lupus-prone MRL/lpr mouse spleen cell cultures. These results indicate that antagonists described herein can suppress immune responses induced by TLR7 and TLR9 agonists. Antagonists may be suitable candidates for treating inflammatory and autoimmune diseases where inappropriate or uncontrolled TLR activation has been implicated.
Wang
Daqing
D
Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, Massachusetts 02139, USA.
Bhagat
Lakshmi
L
Yu
Dong
D
Zhu
Fu-Gang
FG
Tang
Jimmy X
JX
Kandimalla
Ekambar R
ER
Agrawal
Sudhir
S
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*
D017931:DNA Primers; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9