Direct induction of class II molecules by cytomegalovirus in rat heart microvascular endothelial cells is inhibited by ganciclovir (DHPG).
It has been demonstrated both in vivo and in vitro that cytomegalovirus regulates not only MHC class I but also class II antigen expression on vascular endothelial cells. The CMV-linked MHC induction is believed to be involved in acute rejection mechanisms and chronic vasculopathy after transplantation. In this study, we have investigated the effect of 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG; ganciclovir) on CMV-induced class II expression in cultured rat heart microvascular endothelial cells. Two sets of cultured endothelial cells were infected with rat CMV. One of the sets was treated with various concentrations of DHPG and the other set was left untreated. MHC class II antigen expression on the cells was demonstrated by mAbs, by immunoperoxidase (IP) technique, and by FACS. Class II expression was maximal on CMV-infected cells 4-7 days after infection when 77.5 +/- 14.5% of the endothelial cells expressed class II in IP staining. DHPG inhibited the induction of class II, but the inhibitory effect was dependent upon the drug concentration. With increasing concentrations of DHPG (0, 1, 10, 100, and 1000 micrograms/ml), as demonstrated by IP staining (surface and intracellular expression), the frequency of class II-positive cells decreased from 77.5 +/- 14.5% to 58.0 +/- 15.0%, 36.0 +/- 23.0%, 3.0 +/- 3.0%, and 0 +/- 0%, respectively. By FACS (surface expression), the number of class II-positive cells remained somewhat lower, but decreased similarly with increasing concentrations of DHPG (from 37.8 +/- 1.1% to 6.2 +/- 3.1%) (surface expression). Also, the intensity of expression decreased concomitantly. These results suggest that DHPG inhibits CMV-induced class II expression via inhibition of CMV DNA polymerase.
Ustinov
J A
JA
Transplantation Laboratory, University of Helsinki, Finland.
Lahtinen
T T
TT
Bruggeman
C A
CA
Häyry
P J
PJ
Lautenschlager
I T
IT
D000818:Animals; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D009206:Myocardium / Q000276:immunology*; D019384:Nucleic Acid Synthesis Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D000949:Histocompatibility Antigens Class II; D019384:Nucleic Acid Synthesis Inhibitors; D007371:Interferon-gamma; D015774:Ganciclovir