Attenuation of cytomegalovirus-induced endothelial intercellular adhesion molecule-1 mRNA/protein expression and T lymphocyte adhesion by a 2 '-O-methoxyethyl antisense oligonucleotide
Da. Knight et al., Attenuation of cytomegalovirus-induced endothelial intercellular adhesion molecule-1 mRNA/protein expression and T lymphocyte adhesion by a 2 '-O-methoxyethyl antisense oligonucleotide, TRANSPLANT, 69(3), 2000, pp. 417-426
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.