Cytolytic activity against allogeneic human endothelia: resistance of cytomegalovirus-infected cells and virally activated lysis of uninfected cells.
BACKGROUND
Cytomegalovirus (CMV) has been implicated as an exacerbating agent in the development of transplant vascular sclerosis; however, specific etiologic mechanisms remain unresolved. Based upon our previous observations that CMV-infected endothelial cells (ECs) stimulate proliferation and cytokine production by allogeneic T cells, we now test the hypothesis that CMV-driven cytolytic activity may contribute to graft endothelial injury.


METHODS
Limiting dilutions of CMV-seropositive or -seronegative donor-derived T cells were stimulated with CMV-infected or uninfected allogeneic ECs in the presence of interleukin-2. T-cell proliferation was monitored by assay of [3H]thymidine incorporation and stimulated T cells were tested for lytic activity against CMV-infected or uninfected radiolabeled EC targets by 51Cr release assay. Natural killer (NK) cell activity was examined by incubating freshly isolated peripheral blood mononuclear cells with 51Cr-labeled targets, followed by assay of radiolabel release.


RESULTS
CMV-infected ECs were resistant to T cell- and NK-mediated cytolysis regardless of donor serostatus, nature of stimulation, or level of T-cell proliferation. In contrast, although uninfected ECs were unharmed by NK cells, these targets experienced significant lysis by T cells stimulated with either uninfected or CMV-infected ECs.


CONCLUSIONS
These results implicate CMV-infected graft endothelium as a persistent source of infectious virus, a chronic stimulus for potentially destructive host inflammatory activity, and a potential trigger for the generation of lytic injury to uninfected bystander endothelia, suggesting multiple mechanisms by which this virus might perturb equilibrium at the graft/host interface.
Department of Pathology, Ohio State University College of Medicine, Columbus 43210, USA. waldman.1@osu.edu
W J
WJ
Waldman
D A
DA
Knight
P W
PW
Adams
D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D010641:Phenotype; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014184:Transplantation, Homologous / Q000502:physiology
D016877:Oxidants; D006861:Hydrogen Peroxide