T-cell activation response to allogeneic CMV-infected endothelial cells is not prevented by ganciclovir or foscarnet: implications for transplant vascular sclerosis.
BACKGROUND
Cytomegalovirus (CMV), a common infectious complication in transplant recipients, has been implicated as an exacerbating agent in the development of transplant vascular sclerosis (TVS); however, mechanisms defining this role remain to be fully resolved. Our previous studies suggest that CMV-infected graft endothelial cells (EC) can initiate a host T-cell activation cascade, and that cytokines produced as a consequence enhance graft endothelial alloimmunogenicity. Because antiviral therapy has not uniformly attenuated CMV-associated risk of TVS development, we have tested the hypothesis that antiviral agents do not affect T-cell activation by allogeneic CMV-infected EC.


METHODS
Human umbilical vein EC, inoculated with CMV VHL/E and incubated in the presence or absence of ganciclovir (GCV) or foscarnet (PFA), were cocultured with CMV-seropositive or -seronegative donor-derived T cells in the presence of these agents, then labeled with [(3)H]thymidine. Cocultures were harvested, and radiolabel incorporation was assayed by scintillation counting.


RESULTS
Limiting dilution analysis demonstrated that proliferation frequencies of CMV-seropositive donor-derived T cells in response to CMV-infected EC (approximately 80 cells/106, compared with approximately 4 cells/10(6) in response to uninfected EC) were not significantly modified by GCV (approximately 86 cells/10(6)) or PFA (approximately 82 cells/10(6)). Likewise, T-cell proliferation curves generated in response to stimulator cell titrations were essentially identical regardless of drug treatment.


CONCLUSIONS
Results of these experiments suggest that although these drugs limit CMV replication and dissemination, they do not attenuate the inflammatory potential of infected EC, a force that may be a major factor in CMV-mediated exacerbation of the development of TVS.
Waldman
W James
WJ
Department of Pathology, The Ohio State University College of Medicine and Public Health, 166 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210-1218, USA. waldman.1@osu.edu
LeClaire
Joshua D
JD
Knight
Deborah A
DA
D000998:Antiviral Agents / Q000494:pharmacology*; D001808:Blood Vessels / Q000473:pathology*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000472:pathogenicity; D004730:Endothelium, Vascular / Q000166:cytology / Q000821:virology*; D017245:Foscarnet / Q000494:pharmacology*; D015774:Ganciclovir / Q000494:pharmacology*; D006084:Graft Rejection; D006801:Humans; D008213:Lymphocyte Activation; D012598:Sclerosis; D013601:T-Lymphocytes / Q000276:immunology*
D000998:Antiviral Agents; D017245:Foscarnet; D015774:Ganciclovir