NFκB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts

Abstract

Monocyte influx secondary to ischemia-reperfusion conditions the renal allograft to rejection by presentation of antigens and production of cytokines. Monocyte influx depends on NFkappaB-dependent transcription of genes encoding adhesion molecules and chemokines. Here we demonstrate that cationic liposomes containing phosphorothioated oligodeoxynucleotides (ODN) with the kappaB binding site serving as competitive binding decoy, can prevent TNF-alpha-induced NFkappaB 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 NFkappaB activity in 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 NFkappaB decoy ODN prior to transplantation decreases the initial inflammatory response in a stringent, nonimmunosuppressed allogenic transplantation model. Therefore, the NFkappaB 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.

NF-κB in Renal Inflammation

“…The increasing awareness of NF-B diversity in terms of regulatory components and actions calls for more detailed preclinical studies to pinpoint the timeframe and optimal target for potential clinical therapy. 79 Decreased proteinuria Diabetic nephropathy 80 Decreased inflammation AKI, sepsis 39 Decreased inflammation AKI; zymosan 81 Decreased inflammation 5/6 renal ablation model 82 Decreased inflammation AngII-infused renal injury 54,83 Decreased inflammation Parthenolide Glomerulonephritis 56 Decreased inflammation, proteinuria AKI; cisplatin 87 Decreased inflammation, proteinuria AngII-induced kidney injury 67 Decreased inflammation gliotoxin Glomerulonephritis 56 Decreased inflammation, proteinuria DHMEQ Glomerulonephritis 88 Decreased inflammation, proteinuria Specific approaches decoy B ODN Glomerulonephritis, crescentic 90 Decreased inflammation Allogenic renal transplant 92 Decreased inflammation AKI, ischemia-reperfusion 89 Decreased inflammation UUO 91 Decreased inflammation p50 siRNA AKI, sepsis 39 Improved renal function, decreased inflammation p50 knockout AKI, endotoxemia 40 Prolonged inflammation, increased mortality IB␣ super-repressor Protein overload proteinuria 93 Decreased inflammation DHMEQ, dehydroxymethyl-epoxyquinomicin; ODN, oligodeoxynucleotides; PDTC, pyrrolidinedithiocarbamate; siRNA, small interfering RNA; UUO, unilateral ureteral obstruction.…”

Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

“…[13][14][15][16] To date, molecular therapeutic strategies using decoy ODN in glomerulonephritis have successfully focused on the direct effect of decoy ODN for transcription factor E2F or nuclear factor (NF)-kB. [17][18][19][20] These transcription factors are related with cell cycle progression and inflammatory diseases after glomerular injury. Another transcription factor AP-1 binds to AP-1 consensus sequences present in numerous genes associated with cell-proliferative response and ECM production, such as TGF-b1, collagen, and PAI-1.…”

Decoy against nuclear factor-kappa B attenuates myocardial cell infiltration and arterial neointimal formation in murine cardiac allografts

“…7 In the latest studies, NF B decoy attenuates IL-8 which is a polymorphonuclear neutrophil chemotaxin, 25 and in vivo administration of NF B decoy reduces monocyte infiltration and VCAM-1 expression in a rat renal transplant model. 26 Therefore, NF B is one of the key regulators promoting acute rejection; the decoy strategy against NF B may provide …”