NFκB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts

Monocyte influx secondary to ischemia-reperfusion conditions the renal allograft to rejection by presentation of antigens and production of cytokines. Monocyte influx depends on NF kappa B-dependent transcription of genes encoding 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 allogenic rat kidney transplantation model (BN to LEW), we show that perfusing the renal allograft with this decoy prior to transplantation abolishes nuclear NF kappa B activity hi vivo and inhibits VCAM-1 expression in the donor endothelium (P<0.05), At 24 h postreperfusion, periarterial infiltration of monocytes/macrophages was significantly reduced in decoy ODN-treated allografts compared to control allografts (3.7 +/- 0.7 vs. 9.2+/-1.2 macrophages/vessel; P<0.01), At 72 h, there was a reduction of tubulointerstitial macrophage 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 prior to transplantation decreases the initial inflammatory response in a stringent, 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-specific immunosuppressive strategy allowing reduction of systemic immunosuppression on organ transplantation.