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 complications in the transplant recipient. In vitro studies have shown that CMV infection of endothelial cells (EC) results in the direct enhancement of ICAM-1 expression and consequent leukocyte adhesion/activation suggesting mechanisms by which CMV exacerbates graft vascular disease. Although treatment of EC with ICAM-1-specific antisense oligonucleotides has been shown to attenuate ICAM-1 induction under simulated inflammatory conditions (i.e., TNF-alpha), no studies have addressed their effectiveness on virally-induced ICAM-1 expression.


RESULTS
In the current investigation, we show that the progressive increase in endothelial ICAM-1 protein expression that follows inoculation with CMV correlates with a progressive accumulation of ICAM-1 mRNA. Furthermore, we demonstrate that treatment of EC with a partially 2'-O-methoxyethyl modified ICAM-1-specific antisense oligonucleotide before viral inoculation significantly reduces CMV-associated induction of ICAM-1 protein and mRNA expression. Finally, we show that antisense-mediated attenuation in ICAM-1 expression results in a significant reduction of T lymphocyte adhesion to CMV-infected EC monolayers, an interaction that has been implicated in allogeneic T lymphocyte activation, in viral transmission to transiently adherent leukocytes and subsequent hematogenous dissemination.


CONCLUSIONS
These findings demonstrate for the first time that antisense oligonucleotides can effectively reverse virally-induced host cellular protein expression, specifically ICAM-1, as well as consequent T lymphocytes adhesion, thus broadening the potential clinical utility of antisense oligonucleotides.
Knight
D A
DA
Department of Pathology, Ohio State University College of Medicine and Public Health, Columbus 43210-1218, USA.
Briggs
B R
BR
Bennett
C F
CF
Harindranath
N
N
Waldman
W J
WJ
Sedmak
D D
DD
D002448:Cell Adhesion; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016377:Organ Transplantation; D016372:RNA, Antisense / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014181:Transplantation Immunology
D016372:RNA, Antisense; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1