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 exacerbati ng agent in the development of transplant vascular sclerosis; however, specific etiologic mechanisms remain unresolved, Based upon our previ ous observations that CMV-infected endothelial cells (ECs) stimulate p roliferation and cytokine production by allogeneic T cells, we now tes t the hypothesis that CMV driven cytolytic activity may contribute to graft endothelial injury. Methods, Limiting dilutions of CMV seroposit ive or-seronegative donor-derived T cells were stimulated with CMV-inf ected or uninfected allogeneic ECs in the presence of interleukin-a, T cell proliferation was monitored by assay of [H-3]thymidine incorpora tion and stimulated T cells were tested for lytic activity against CMV -infected or uninfected radiolabeled EC targets by Cr-51 release assay . Natural killer (NK) cell activity was examined by incubating freshly isolated peripheral blood mononuclear cells with Cr-51-labeled target s, 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 eithe r uninfected or CMV-infected ECs. Conclusions. These results implicate CMV-infected graft endothelium as a persistent source of infectious v irus, 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 .