Effect of cytomegalovirus on an experimental model of chronic renal allograft rejection under triple-drug treatment in the rat.
BACKGROUND
Cytomegalovirus (CMV) infection is thought to be a risk factor of chronic rejection. In clinical studies and animal models, mainly concerning graft vasculopathy, CMV has been demonstrated to enhance allograft arteriosclerosis. In this study we have investigated the effect of CMV on the early inflammatory response and graft histology in an experimental model of renal transplantation in a rat strain combination that develops chronic rejection under triple-drug immunosuppression.


METHODS
Renal transplantations were performed in a rat strain combination of DA-->BN receiving triple-drug treatment (2 mg/kg methylprednisolone, 2 mg/kg azathioprine, 5 mg/kg cyclosporine daily subcutaneously). One group of immunosuppressed animals was infected with rat CMV, the Maastricht strain (10(5) plaque-forming units intraperitoneally), and the other group was left uninfected. As a positive control for alloresponse, one group of recipients received neither immunosuppression nor virus. Syngenic transplantations with triple-drug treatment and CMV were used as negative controls. The grafts were monitored by frequent ultrasound-guided fine-needle aspiration biopsies, and the intragraft inflammation was quantified in detail by the increment method and expressed in corrected increment units (CIU). Graft histology was performed in parallel.


RESULTS
Nonimmunosuppressed animals developed acute rejection with a high peak of inflammation (7.9+/-3.2 CIU), a typical blast response, and lymphocytosis followed by infiltration of macrophages and necrosis within 7 days. Triple drug-treated animals had a short, mild inflammatory response (3.3+/-1.4 CIU at the peak) in the graft 3-5 days after transplantation but ended up with histological changes characteristic of chronic rejection with vasculopathy and fibrosis 40-60 days later. Triple drug-treated animals with CMV demonstrated a significantly stronger inflammation (4.5+/-1.8 CIU, P<0.01) than those without, and lymphoid activation continued longer and was followed by infiltration of macrophages in the graft. CMV infection of the graft was demonstrated by viral culture and antigen detection. In histology, chronic rejection with intimal thickening of arteries and arterioles and medial necrosis of large arteries was seen at 14 days, ending up with remarkable graft fibrosis within 20 days after transplantation.


CONCLUSIONS
CMV prolonged and increased graft inflammation and accelerated chronic rejection of renal allografts under triple-drug treatment.
Lautenschlager
I
I
Department of Virology, Helsinki University Central Hospital, Finland.
Soots
A
A
Krogerus
L
L
Kauppinen
H
H
Saarinen
O
O
Bruggeman
C
C
Ahonen
J
J
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D001707:Biopsy, Needle; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D003586:Cytomegalovirus Infections / Q000150:complications*; D006084:Graft Rejection / Q000382:microbiology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D051381:Rats; D011914:Rats, Inbred BN; D011919:Rats, Inbred Strains
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001379:Azathioprine; D008775:Methylprednisolone