Therapeutic potential of immunosuppressive oligonucleotides expressing TTAGGG motifs

Synthetic oligodeoxynucleotides (ODNs) expressing immunosuppressive TTAGGG motifs downregulate the production of pro-inflammatory and Th1 cytokines. We are interested in the ability of these suppressive ODNs to slow or prevent the development of diseases characterized by pathologic levels of immune stimulation including autoimmune diseases and septic shock. In murine models of arthritis, lupus, LPS-induced toxic shock, and inflammatory diseases of several organs, treatment with suppressive ODNs significantly reduced disease severity. These beneficial effects were accompanied by reductions in serum autoantibody and/or inflammatory cytokine levels. While the mechanism underlying these protective effects is incompletely understood, suppressive ODNs bind to and prevent the phosphorylation of STAT1 and STAT4, thereby blocking the signaling cascade central to the initiation and/or perpetuation of some inflammatory disease states. These findings suggest that suppressive ODN may find use in the treatment of acute and chronic diseases characterized by excessive immune stimulation.