Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

Authors

  • Timi Martelius M.D.,

    Corresponding author
    1. Fourth Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
    2. Department of Virology, Helsinki University Central Hospital, Helsinki, Finland
    • Transplant Unit Research Laboratory, Fourth Department of Surgery, Helsinki University Central Hospital, Kasarmikatu 11-13, 00130 Helsinki, Finland. Fax: 358-9-174975.
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  • Leena Krogerus,

    1. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
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  • Krister Höckerstedt,

    1. Fourth Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
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  • Cathrien Bruggeman,

    1. Department of Medical Microbiology, University of Limburg, Maastricht, The Netherlands
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  • Irmeli Lautenschlager

    1. Department of Virology, Helsinki University Central Hospital, Helsinki, Finland
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Abstract

It has been suggested that cytomegalovirus (CMV) infection is involved in allograft rejection. In liver transplantation, it has been suggested that CMV is associated with the development of vanishing bile duct syndrome (VBDS), and persistent CMV has been found in liver grafts that develop chronic rejection. In this experimental study, the effect of rat CMV (RCMV) infection on intragraft changes was investigated in a rat model of acute liver allograft rejection. Liver transplantations were performed in a rat strain combination of PVG (RT1c) → BN (RT1n). No immunosuppression was given. One group of animals was infected with RCMV Maastricht Strain (105 plaque-forming units, intraperitoneally), and another group was left uninfected. The grafts were examined histologically after the rats were killed on postoperative days 7 through 9 at the early phase and days 20 through 30 at the late phase of rejection. Immunohistochemical studies were performed to demonstrate the immunological activation markers major histocompatibility complex class II and interleukin 2 receptors, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their ligands. RCMV infection was demonstrated from the grafts by culture and direct antigen detection. In liver allografts undergoing acute rejection, CMV significantly increased portal inflammation and caused more severe bile duct damage than in the uninfected grafts. CMV was also linked to the induction of VCAM-1 in the endothelial cells. The ongoing infection was found to vary over time in the different structures of the liver grafts, including the vascular endothelium and bile ducts. Our results support an association between CMV infection and the immunological mechanisms of rejection, as well as the role of CMV in the development of bile duct damage in liver allografts.

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