title: Cytomegalovirus infection-enhanced chronic kidney allograft rejection is linked with intercellular adhesion molecule-1 expression.
abstract: In human kidney allografts, association of acute rejection and glomerulopathy with cytomegalovirus (CMV) infection has been demonstrated. To investigate the effect of CMV infection on the development of experimental chronic kidney allograft rejection, heterotopic kidney allografts from DA (Ag-B4, RT1a1) rat donors to WF (Ag-B2, RT1u) rat recipients were used. The animals received cyclosporine A (CsA) 5 mg/kg/day s.c. either for 1 or 12 weeks. Two groups of recipients were infected with 10(5) plaque-forming units of rat CMV (RCMV) and two other groups were left noninfected and used as controls. The grafts were removed 12 weeks after transplantation for histology and immunohistochemistry. RCMV infection significantly enhanced the development of chronic kidney allograft rejection in rats on continuous CsA the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025), the glomerular mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01), the extent of endothelial cell swelling (P < 0.025) and intimal proliferation (P < 0.025) in the graft vasculature, and the extent of tubular epithelial atrophy (P < 0.025). Chronic allograft damage index (CADI) was significantly increased to 4.3 +/- 0.8 in RCMV-infected allografts, compared to 0.8 +/- 0.4 in noninfected (P < 0.02). In addition, RCMV infection significantly increased the number of acute rejection episodes (serum creatinine > 200 mumol/liter, P < 0.05) and almost doubled the end-stage serum creatinine. RCMV infection significantly increased ICAM-1 expression on the vascular endothelium (P < 0.05) and tubular epithelial cells (P < 0.01), and was linked with enhanced interstitial, glomerular, and tubular inflammation. In 80% of allografts on continuous CsA, RCMV antigens could be observed in sporadic inflammatory cells one week after infection and in tubular epithelial cells at 12 weeks. In heavily inflamed allografts where the CsA treatment was discontinued at one week, enhancement of RCMV infection on the histological changes attributable to chronic kidney allograft rejection could not be demonstrated. Our results show that during CsA immunosuppression, RCMV infection enhances chronic kidney allograft rejection associated with increased interstitial inflammation as well as vascular endothelial and tubular epithelial ICAM-1 expression.
authors.affiliation: Transplantation Laboratory, University of Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Yilmaz
authors.forename: P K
authors.initials: PK
authors.lastname: Koskinen
authors.forename: E
authors.initials: E
authors.lastname: Kallio
authors.forename: C A
authors.initials: CA
authors.lastname: Bruggeman
authors.forename: P J
authors.initials: PJ
authors.lastname: Häyry
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000008:administration & dosage; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006084:Graft Rejection / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D051381:Rats; D011920:Rats, Inbred WF; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine