TRIPLE-DRUG IMMUNOSUPPRESSION SIGNIFICANTLY REDUCES IMMUNE ACTIVATIONAND ALLOGRAFT ARTERIOSCLEROSIS IN CYTOMEGALOVIRUS-INFECTED RAT AORTICALLOGRAFTS AND INDUCES EARLY LATENCY OF VIRAL-INFECTION

The effect of triple drug immunosuppression (cyclosporine A 10 mg/kg/d ay + methylprednisolone 0.5 mg/kg/day + azathioprine 2 mg/kg/day) on r at cytomegalovirus (RCMV)-enhanced allograft arteriosclerosis was inve stigated applying WF (AG-B2, RT1(v)) recipients of DA (AG-B4, RT1(a)) aortic allografts. The recipients were inoculated intraperitoneally wi th 10(5) plaque-forming units of RCMV 1 day after transplantation or l eft non-infected. The grafts were removed on 7 and 14 days, and at 1, 3, and 6 months after transplantation. The presence of viral infection was demonstrated by plaque assays, cell proliferation by [H-3]thymidi ne autoradiography, and vascular wall alterations by quantitative hist ology and immunohistochemistry. Triple drug immunosuppression reduced the presence of infectious virus in plaque assays and induced early la tency of viral infection. It significantly reduced the peak adventitia l inflammatory response (P < 0.05) and reduced and delayed intimal nuc lear intensity and intimal thickening CP < 0.05) in RCMV-infected allo grafts. The proliferative response of smooth muscle cells was reduced by triple drug immunosuppression to 50% of that observed in nonimmunos uppressed RCMV-infected allografts, but still the proliferative peak r esponse was seen at 1 month. Only low level immune activation, ie, the expression of interleukin-2 receptor (P < 0.05) and MHC class II, was observed under triple drug immunosuppression in the adventitia of RCM V-infected allografts, whereas there was no substantial change in the phenotypic distribution of inflammatory cells. In conclusion, although RCMV infection significantly enhances allograft arteriosclerosis also in immunosuppressed allografts, triple drug immunosuppression has no additional detrimental effect but rather a protective one on vascular wall histology. These results further suggest that RCMV-enhanced allog raft arteriosclerosis may be an immunopathological condition linked to the host immune response toward the graft and/or the virus rather tha n a direct virus-induced phenomenon.