Attenuation of cytomegalovirus-induced endothelial intercellular adhesion molecule-1 mRNA/protein expression and T lymphocyte adhesion by a 2 '-O-methoxyethyl antisense oligonucleotide

Background. Intercellular adhesion molecule-1 (ICAM-1) is strongly induced under inflammatory conditions associated with allograft rejection, thereby promoting leukocyte recruitment and activation at the site of inflammation. Enhancement of ICAM-1 expression can also be the result of viral infection , in particular human cytomegalovirus (CMV), a frequent source of complicat ions in the transplant recipient. In vitro studies have shown that CMV infe ction of endothelial cells (EC) results in the direct enhancement of ICAM-1 expression and consequent leukocyte adhesion/activation suggesting mechani sms by which CMV exacerbates graft vascular disease. Although treatment of EC with ICAM-1-specific antisense oligonucleotides has been shown to attenu ate ICAM-1 induction under simulated inflammatory conditions (i.e., TNF-alp ha), no studies have addressed their effectiveness on virally-induced ICAM- 1 expression. Results. En the current investigation, we show that the progressive increas e in endothelial ICAM-1 protein expression that follows inoculation with CM V correlates with a progressive accumulation of ICAM-1 mRNA. Furthermore, w e demonstrate that treatment of EC with a partially 2'-O-methoxyethyl modif ied ICAM-1-specific antisense oligonucleotide before viral inoculation sign ificantly reduces CMV-associated induction of ICAM-1 protein and mRNA expre ssion. Finally, we show that antisense-mediated attenuation in ICAM-1 expre ssion results in a significant reduction of T lymphocyte adhesion to CMV-in fected EC monolayers, an interaction that has been implicated in allogeneic T lymphocyte activation, in viral transmission to transiently adherent leu kocytes and subsequent hematogenous dissemination. Conclusions. These findings demonstrate for the first time that antisense o ligonucleotides can effectively reverse virally-induced host cellular prote in expression, specifically ICAM-1, as well as consequent T lymphocytes adh esion, thus broadening the potential clinical utility of antisense oligonuc leotides.