NF kappa B decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts

Monocyte influx secondary to ischemia-reperfusion conditions the renal allo graft to rejection by presentation of antigens and production of cytokines. Monocyte influx depends on NF kappa B-dependent transcription of genes enc oding adhesion molecules and chemokines, Here we demonstrate that cationic liposomes containing phosphorothioated oligodeoxynucleotides (ODN) with the kappa B binding site serving as competitive binding decoy, can prevent TNF -alpha-induced NF kappa B activity in endothelial cells in vitro, In an all ogenic rat kidney transplantation model (BN to LEW), we show that perfusing the renal allograft with this decoy prior to transplantation abolishes nuc lear NF kappa B activity hi vivo and inhibits VCAM-1 expression in the dono r endothelium (P<0.05), At 24 h postreperfusion, periarterial infiltration of monocytes/macrophages was significantly reduced in decoy ODN-treated all ografts compared to control allografts (3.7 +/- 0.7 vs. 9.2+/-1.2 macrophag es/vessel; P<0.01), At 72 h, there was a reduction of tubulointerstitial ma crophage infiltration in decoy ODN-treated kidneys compared to controls (75 .6+/-13.9 vs. 120.0+/-11.2 macrophages/tubulointerstitial area; P<0.05), In conclusion, perfusion of the renal allograft with NF kappa B decoy ODN pri or to transplantation decreases the initial inflammatory response in a stri ngent, nonimmunosuppressed allogenic transplantation model. Therefore, the NF kappa B decoy approach may be useful to explore the role of endothelium and macrophages in graft rejection and may be developed into a graft-specif ic immunosuppressive strategy allowing reduction of systemic immunosuppress ion on organ transplantation.