NFkappaB 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 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.
Vos
I H
IH
Departments of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands.
Govers
R
R
Gröne
H J
HJ
Kleij
L
L
Schurink
M
M
De Weger
R A
RA
Goldschmeding
R
R
Rabelink
T J
TJ
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000235:genetics* / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014161:Transduction, Genetic; D014184:Transplantation, Homologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D019010:Vascular Cell Adhesion Molecule-1