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 fa ctor of chronic rejection. In clinical studies and animal models, main ly concerning graft vasculopathy, CMV has been demonstrated to enhance allograft arteriosclerosis, In this study we have investigated the ef fect of CMV on the early inflammatory response and graft histology in an experimental model of renal transplantation in a rat strain combina tion that develops chronic rejection under triple-drug immunosuppressi on. Methods. Renal transplantations were performed in a rat strain com bination of DA-->BN receiving triple-drug treatment (2 mg/kg methylpre dnisolone, 2 mg/kg azathioprine, 5 mg/kg cyclosporine daily subcutaneo usly). 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 a lloresponse, one group of recipients received neither immunosuppressio n nor virus. Syngenic transplantations with triple-drug treatment and CMV were used as negative controls. The grafts were monitored by frequ ent ultrasound-guided fine-needle aspiration biopsies, and the intragr aft inflammation was quantified in detail by the increment method and expressed in corrected increment units (CIU). Graft histology was perf ormed in parallel. Results. Nonimmunosuppressed animals developed acut e rejection with a high peak of inflammation (7.9+/-3.2 CIU), a typica l blast response, and lymphocytosis followed by infiltration of macrop hages and necrosis within 7 days. Triple drug-treated animals had a sh ort, mild inflammatory response (3.3+/-1.4 CIU at the peak) in the gra ft 3-5 days after transplantation but ended up with histological chang es 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 w ith remarkable graft fibrosis within 20 days after transplantation. Co nclusion. CMV prolonged and increased graft inflammation and accelerat ed chronic rejection of renal allografts under triple-drug treatment.