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Inbred DA (AG-B4, RT1 a) and WF (AG-B2, RT1') rats were used as donors and recipients of aortic allografts. The recipient rats were inoculated i.p. either on day 1 (early infection) or on day 60 (late infection) with iOs plaque-forming units of rat cytomegalovirus (RCMV). The control rats were left noninfected. The presence of viral infection was demonstrated by plaque assays from biopsies of the salivary glands, liver, and spleen at sacrifice. The rats received 300 gCi 13H Ithymidine by i.v. injection 3 h before sacrifice, and the grafts were removed at various time points for histology, immunohistochemistry, and autoradiography. RCMV infection significantly enhanced the generation of allograft arteriosclerosis. Infection at the time of transplantation had two important effects. First, the infection was associated with an early, prominent inflammatory episode and proliferation of inflammatory cells in the allograft adventitia. Second, the viral infection doubled the proliferation rate of smooth muscle cells and the arteriosclerotic alterations in the intima. In late infection the impact of RCMV infection on the allograft histology was nearly nonexistent. RCMV infection showed no effect in syngeneic grafts. These results suggest that early infection is more important to the generation of accelerated allograft arteriosclerosis than late infection, and that an acute alloimmune response must be associated with virus infection, to induce accelerated allograft arteriosclerosis. RCMVinfected aortic allografts, as described here, provide the first experimental model to investigate the interaction between the virus and the vascular wall of the transplant. (J. Clin. Invest. 1993. 92:549-558.)

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The etiology of chronic allograft rejection is multifactorial. 8 Cytomegalovirus (CMV) infection is one of the sug-Among the risk factors are histocompatibility, frequency of gested risk factors for chronic allograft rejection. Clini-acute rejection episodes, long ischemia time, and infections. cal and experimental studies have shown that CMV is An association between viral infection, particularly that of somehow implicated in rejection mechanisms and in the cytomegalovirus (CMV) infection, and chronic rejection has generation of graft arteriosclerosis, characteristic of been suggested. In heart transplantation, chronic rejection chronic rejection. In liver transplantation, there is also manifests as allograft arteriosclerosis, and increased graft evidence of an association between CMV and vanishing arteriopathy has been found in recipients with previous CMV bile duct-syndrome (VBDS), which is characteristic of infection. 9-11 In kidney transplantation, CMV has been re-chronic liver allograft rejection. In this study, the role ported to trigger rejection 12,13 by inducing major histocompat-of posttransplant CMV infection and of acute rejection ibility complex antigens, especially class II molecules. 13 CMV in the patients with irreversible, histologically con-is also suggested to be involved in late acute renal allograft firmed chronic liver rejection with VBDS and vasculopa-rejections. 14 In liver transplantation, a higher incidence of thy was analyzed. Ten of 200 (5%) consecutive liver trans-chronic rejection has been observed in patients with verified plants were lost due to chronic rejection, from between posttransplant CMV infection. 3 An association between CMV 5 and 28 months from transplantation. In these 10 pa-infection and chronic liver rejection with VBDS has been sug-tients, acute rejections were frequent, and nine of ten gested, 15,16 although other investigators have been unable to patients had at least one episode of rejection early after demonstrate a definite association. 17 The persistence of CMV-transplantation. All patients (10 of 10) had a history of DNA in the hepatocytes of liver grafts in VBDS has been CMV infection usually following acute rejection. To in-recently demonstrated. 16 vestigate the role of CMV in chronic rejection, nine avail-In this retrospective study, the aim was to investigate the able removed grafts were examined for the presence of role of posttransplant CMV infection in patients with chronic the CMV genome by DNA-hybridization in situ using a liver rejection and VBDS whether CMV-DNA is still found biotinylated CMV-DNA probe. Persistent CMV-DNA was in the explanted allografts and, if so, in which parenchymal found in all of those available grafts with chronic rejec-components of the liver. To detect the viral genome in frozen tion. CMV-DNA was strongly expressed in the remaining sections of the liver grafts, in situ hybridization and a biotin-bile ducts and moderately expressed in the endothelial ylated CMV-DNA probe were used. cells of the vascular structures, the CMV...

Background Major risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated.Methods and Results Aortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with