INHIBITION OF THE P50 (NF-KAPPA-B1) SUBUNIT OF NF-KAPPA-B BY PHOSPHOROTHIOATE-MODIFED ANTISENSE OLIGODEOXYNUCLEOTIDES REDUCES NF-KAPPA-B EXPRESSION AND IMMUNOGLOBULIN-SYNTHESIS IN MURINE B-CELLS

NF-kappa B is a regulatory protein of immune response genes and a cand idate for targeting in immunosuppressive therapy. NF-kappa B proteins are formed hom components of which p50 (NF kappa B1) is a subunit. By targeting p50 gene expression with specific antisense 3' phosphorothio ate-oligodeoxynucleotides (3' PS-ODNs), an effect upon NF-kappa B regu lation and immunoglobulin synthesis in murine B cells was achieved. A 49% decrease in p50 protein was induced by treatment of WEHI 231 B cel ls with p50 antisense 3' PS-ODNs and not by control 3' PS-ODNs. p50 an tisense specifically reduced the expression of NF-kappa B by 51%, but not the transcription factor, Oct-1. in the BXSB murine model of autoi mmunity, p50 antisense inhibited NF-kappa B expression and total IgM a nd IgG synthesis, but, more importantly, dsDNA antibodies were reduced 90%. These results validate the use of p50 antisense to reduce NF-kap pa B expression and, by downregulating the immune response, has applic ation in the treatment of autoimmune disorders. (C) 1997 Academic Pres s.