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NFB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts

INGRID H. C. VOS^*, ROLAND GOVERS, HERMANN-JOSEF GRÖNE, LIVIO KLEIJ, MEREL SCHURINK^*, ROEL A. DE WEGER^§, ROEL GOLDSCHMEDING^§ and TON J. RABELINK¹

^* Departments of Nephrology and Hypertension,
Vascular Medicine, and
^§ Pathology, University Medical Center, Utrecht, The Netherlands; and
German Cancer Research Center, Heidelberg, Germany

¹Correspondence: Department of Vascular Medicine, University Medical Center, G02.228, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail T.RABELINK{at}DIGD.AZU.NL

Monocyte influx secondary to ischemia-reperfusion conditions the renal allograft to rejection by presentation of antigens and production of cytokines. Monocyte influx depends on NFB-dependent transcription of genes encoding adhesion molecules and chemokines. Here we demonstrate that cationic liposomes containing phosphorothioated oligodeoxynucleotides (ODN) with the B binding site serving as competitive binding decoy, can prevent TNF--induced NFB 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 NFB 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 NFB decoy ODN prior to transplantation decreases the initial inflammatory response in a stringent, nonimmunosuppressed allogenic transplantation model. Therefore, the NFB 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., Govers, R., Gröne, H.-J., Kleij, L., Schurink, M., de Weger, R., Goldschmeding, R., Rabelink, T. J. NFB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts

Key Words: transplantation • adhesion molecules • macrophages • endothelium

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