Therapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs.
Synthetic oligodeoxynucleotides (ODNs) expressing immunosuppressive TTAGGG motifs downregulate the production of proinflammatory and Th1 cytokines. The ability of these "suppressive ODNs" to slow or prevent the development of diseases characterized by over-exuberant immune stimulation was examined. Suppressive ODNs significantly reduced disease severity in murine models of arthritis, lupus, and LPS-induced toxic shock. These beneficial effects were accompanied by a significant reduction in serum autoantibody and cytokine levels. Underlying these protective effects was the ability of suppressive ODNs to bind to and prevent the phosphorylation of STAT1 and STAT4, thereby blocking the signaling cascade central to the initiation and/or perpetuation of these disease states. These findings suggest that suppressive ODNs might find use in the treatment of acute and chronic diseases characterized by excessive immune stimulation.
Klinman
Dennis M
DM
Section of Retroviral Research, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. klinman@cber.fda.gov
Gursel
Ihsan
I
Klaschik
Sven
S
Dong
Li
L
Currie
Debbie
D
Shirota
Hidekazu
H
D020816:Amino Acid Motifs; D000818:Animals; D001168:Arthritis / Q000628:therapy; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry*; D008177:Lupus Vulgaris / Q000628:therapy; D051379:Mice; D009841:Oligonucleotides / Q000737:chemistry / Q000627:therapeutic use*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D016207:Cytokines; D007166:Immunosuppressive Agents; D009841:Oligonucleotides; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor