CYTOKINE-MEDIATED INDUCTION OF ENDOTHELIAL ADHESION MOLECULE AND HISTOCOMPATIBILITY LEUKOCYTE ANTIGEN EXPRESSION BY CYTOMEGALOVIRUS-ACTIVATED T-CELLS

Cytomegalovirus (CMV) has been associated with allograft rejection and transplantation-associated arteriosclerosis. CMV infects endothelium, the interface between allograft tissue and the host immune system; ho wever, mechanisms by which such interaction might exacerbate the rejec tion process remain unresolved. Here we test the hypothesis that host immune activity, triggered by CMV-infected graft endothelial cells (EC s), can result in the production of cytokines capable of enhancing the alloimmunogenicity of nearby uninfected endothelia. To model these ph enomena in vitro, confluent monolayers of ECs derived from human umbil ical vein or adult gonadal vein were incubated 5 days beneath trans-we ll culture inserts containing CMV-seropositive or CMV-seronegative don or-derived CD3(+) or CD4(+) T cells alone or in combination with CMV-i nfected or uninfected allogeneic ECs. The extent of T cell proliferati on was determined by [H-3]thymidine labeling of trans-well contents af ter transfer to microliter plates. endothelial responses to soluble fa ctors elaborated by CMV-activated T cells were determined by immunohis tochemical staining and immunofluorescence flow cytometric analysis of underlying EC monolayers. Results of experiments with CMV-seropositiv e donor-derived CD4(+) T cells demonstrated enhancement of ICAM-1 and histocompatibility leukocyte antigen class 1, as well as induction of histocompatibility leukocyte antigen DR on ECs incubated beneath T cel l/EC/CMV trans-well co-cultures. Total (CD3(+)) T cells co-cultured wi th EC/CMV induced VCAM-1 as well. Furthermore, dicated a strong prolif erative response. Endothelial responses to T cells alone or in combina tion with uninfected ECs were minimal, and T cells cultured under thes e conditions showed little proliferative activity. Similarly, little o r no endothelial responses were apparent in monolayers beneath trans-w ells containing T cells isolated from CMV-seronegative individuals reg ardless of the CMV status of stimulator ECs. Finally, experiments empl oying blocking antibodies identified interferon-gamma and tumor necros is factor-alpha as inducing agents in this co-culture system. These fi ndings suggest that allograft endothelium harboring CMV has the potent ial to activate host T cells and that the consequent release of cytoki nes shows potential to raise surrounding endothelia to a fully activat ed, highly immunogenic state. Results of these studies thus provide in sight into mechanisms that help elucidate the association between CMV and transplantation-associated arteriosclerosis and/or allograft rejec tion.