USE OF PHOSPHOROTHIOATE-MODIFIED OLIGODEOXYNUCLEOTIDES TO INHIBIT NF-KAPPA-B EXPRESSION AND LYMPHOCYTE FUNCTION

NF-kappa B is a potential target for immunosuppressive therapy. Tao me thods were evaluated to inhibit NF-kappa B: the antisense (AS) approac h in which single-stranded oligodeoxynucleotides (ODNs) bind the mRNA for the RelA subunit of NF-kappa B and the transcription factor decoy (TFD) approach in which double-stranded ODNs hind the NF-kappa B prote in. AS and TFD inhibited NF-kappa B binding and decreased total IgG an d. anti-dsDNA antibody production in splenocytes from the BXSB/Yaa aut oimmune mouse strain. TNF-alpha expression was reduced by AS and TFD, as were the levels of IL-2, But AS effects did not last beyond 24 h, w hereas TFD inhibited cytokine production after 72 h. AS had no effect upon IL-6, while the TFD reduced the secretion of IL-6. Therefore, the suppression of immune response mediators by AS of TFD, through inhibi tion of NF-kappa B, is substantial, These inhibitors can serve as nove l choices for therapy in the treatment of autoimmune disorders, (C) 19 98 Academic Press.