INFLAMMATION AND INFLAMMATORY BOWEL DISEASE

ICAM-1 and VCAM-1 antisense oligonucleotides attenuate in vivo leucocyte adherence and inflammation in rat inflammatory bowel disease

E Rijcken^1,, C F Krieglstein^1,, C Anthoni¹, M G Laukoetter¹, R Mennigen¹, H U Spiegel¹, N Senninger¹, C F Bennett² and G Schuermann¹

¹ Department of General Surgery, Westphalian Wilhelms-University, Muenster, Germany
² ISIS Pharmaceuticals, Carlsbad, CA 92008, USA

Correspondence to:
Correspondence to:
Dr C F Krieglstein, Department of General Surgery, Westphalian Wilhelms-University, Waldeyerstr 1, D-48149 Muenster, Germany;
krieglstein{at}uni-muenster.de

Background: Recruitment of circulating cells to the inflamed intestine is modulated by adhesion molecules expressed on the surface of both leucocytes and endothelial cells.

Aims: The objective of this study was to test whether 2`-O-methoxyethyl chimeric antisense oligonucleotides directed against endothelial intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) can downregulate leucocyte-endothelial interactions and thereby attenuate inflammation in rat experimental ileitis.

Methods: Indomethacin (7.5 mg/kg ) was injected subcutaneously into Sprague-Dawley rats 48 and 24 hours prior to intravital microscopy. Animals were treated with either ICAM-1 (ISIS 17470), VCAM-1 (ISIS 18155), or scrambled control antisense oligonucleotides administered subcutaneously or intravenously in parallel with indomethacin. Leucocyte trafficking was observed in ileal submucosal collecting venules. Macroscopic and histological grades of inflammation were measured 48 hours after the first indomethacin application. ICAM-1 and VCAM-1 expression in ileal submucosal venules was detected by immunohistochemistry.

Results: Intravenous administration of ICAM-1 oligonucleotides 2 mg/kg (rolling leucocytes 5.7 (2.4)/0.01 mm² endothelial surface, adherent leucocytes 0.8 (1.1)) and VCAM-1 oligonucleotides 8 mg/kg (9.2 (4.4), 0.6 (0.8)) significantly reduced leucocyte adhesion compared with diseased controls (27.8 (5.3), 14 (4.4)) in a dose dependent manner whereas subcutaneous treatment did not. Correspondingly, macroscopic and histological inflammation was significantly decreased. ICAM-1 oligonucleotides markedly reduced endothelial ICAM-1 expression while VCAM-1 oligonucleotides clearly diminished endothelial VCAM-1 expression.

Conclusions: Both ICAM-1 and VCAM-1 2`-O-methoxyethyl chimeric antisense oligonucleotides attenuate rat ileitis by downregulation of leucocyte adherence and thus are potential candidates for anti-inflammatory treatment in inflammatory bowel disease.

Keywords: inflammatory bowel disease; antisense oligonucleotides; cell adhesion molecules; intercellular adhesion molecule; vascular cell adhesion molecule

Abbreviations: FITC, fluorescein isothiocyanate; IBD, inflammatory bowel disease; ICAM-1, intercellular adhesion molecule 1; IL-1, interleukin 1; IVM, intravital microscopy; LFA-1, leucocyte function antigen 1; TNF-, tumour necrosis factor ; VLA-1, very late antigen 1; VCAM-1, vascular cell adhesion molecule 1; PBS, phosphate buffered saline

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