Suppressive oligodeoxynucleotides inhibit Th1 differentiation by blocking IFN-gamma- and IL-12-mediated signaling.
Repetitive TTAGGG motifs present at high frequency in mammalian telomeres can suppress Th1-mediated immune responses. Synthetic oligonucleotides (ODN) containing TTAGGG motifs mimic this activity and have proven effective in the prevention/treatment of certain Th1-dependent autoimmune diseases. This work explores the mechanism by which suppressive ODN block the induction of Th1 immunity. Findings indicate that these ODN inhibit IFN-gamma-induced STAT1 phosphorylation and IL-12-induced STAT3 and STAT4 phosphorylation. As a result, T-bet expression is reduced as is the maturation of naive CD4+ cells into Th1 effectors. These changes indirectly support the generation of Th2-dominated immune responses. Suppressive ODN may thus represent a novel approach to influence the Th1:Th2 balance in vivo.
Section of Retroviral Immunology, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892, USA.
Hidekazu
H
Shirota
Mayda
M
Gursel
Dennis M
DM
Klinman
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D018417:Th1 Cells / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma