title: Triple drug immunosuppression significantly reduces immune activation and allograft arteriosclerosis in cytomegalovirus-infected rat aortic allografts and induces early latency of viral infection.
abstract: The effect of triple drug immunosuppression (cyclosporine A 10 mg/kg/day+methylprednisolone 0.5 mg/kg/day+azathioprine 2 mg/kg/day) on rat cytomegalovirus (RCMV)-enhanced allograft arteriosclerosis was investigated applying WF (AG-B2, RT1v) recipients of DA (AG-B4, RT1a) aortic allografts. The recipients were inoculated intraperitoneally with 10(5) plaque-forming units of RCMV 1 day after transplantation or left noninfected. 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 [3H]thymidine autoradiography, and vascular wall alterations by quantitative histology and immunohistochemistry. Triple drug immunosuppression reduced the presence of infectious virus in plaque assays and induced early latency of viral infection. It significantly reduced the peak adventitial inflammatory response (P < 0.05) and reduced and delayed intimal nuclear intensity and intimal thickening (P < 0.05) in RCMV-infected allografts. The proliferative response of smooth muscle cells was reduced by triple drug immunosuppression to 50% of that observed in nonimmunosuppressed RCMV-infected allografts, but still the proliferative peak response 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 RCMV-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 allograft arteriosclerosis may be an immunopathological condition linked to the host immune response toward the graft and/or the virus rather than a direct virus-induced phenomenon.
authors.affiliation: Transplantation Laboratory, University of Helsinki, Finland.
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
authors.forename: J H
authors.initials: JH
authors.lastname: Bruning
authors.forename: C A
authors.initials: CA
authors.lastname: Bruggeman
authors.forename: I T
authors.initials: IT
authors.lastname: Lautenschlager
authors.forename: P J
authors.initials: PJ
authors.lastname: Häyry
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000453:epidemiology* / Q000209:etiology / Q000517:prevention & control; D001379:Azathioprine / Q000494:pharmacology*; D002455:Cell Division; D016572:Cyclosporine / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000150:complications*; D004247:DNA / Q000378:metabolism; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D006084:Graft Rejection / Q000517:prevention & control; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007109:Immunity / Q000276:immunology*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015994:Incidence; D007694:Killer Cells, Natural / Q000473:pathology; D008775:Methylprednisolone / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D051381:Rats; D011920:Rats, Inbred WF; D011930:Reaction Time; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000473:pathology; D013936:Thymidine / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects*; D014316:Tritium
chemical_list: D004279:DNA, Viral; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D014316:Tritium; D016572:Cyclosporine; D004247:DNA; D001379:Azathioprine; D013936:Thymidine; D008775:Methylprednisolone