Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.
BACKGROUND
Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model.


METHODS
One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined.


RESULTS
In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells.


CONCLUSIONS
Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
Martelius
T
T
Department of Surgery, Helsinki University Hospital, Finland. tmarteli@helsinki.fi
Scholz
M
M
Krogerus
L
L
Höckerstedt
K
K
Loginov
R
R
Bruggeman
C
C
Cinatl
J
J
Doerr
H W
HW
Lautenschlager
I
I
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology*; D003676:Deferoxamine / Q000494:pharmacology*; D006084:Graft Rejection / Q000150:complications; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000821:virology; D016031:Liver Transplantation; D009393:Nephritis / Q000209:etiology / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D015815:Cell Adhesion Molecules; D014409:Tumor Necrosis Factor-alpha; D003676:Deferoxamine