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.

Synergistic induction of intercellular adhesion molecule-1 by the human cytomegalovirus transactivators IE2p86 and pp71 is mediated via an Sp1-binding site

“…Investigations examining the influence of HCMV on immunomodulating molecules on infected cells identified a marked increase in ICAM-1 cellsurface expression as well as mRNA levels in endothelial cells and fibroblasts (Grundy & Downes, 1993;Sedmak et al, 1994;Ito et al, 1995;Burns et al, 1999;Knight et al, 1999Knight et al, , 2000. The in vivo relevance of cytomegalovirus-mediated ICAM-1 induction in the development of vascular lesions is strongly supported by results obtained with the rat model, where it has been shown that prolonged expression of ICAM-1 after infection of kidney allograft recipients with rat cytomegalovirus correlated with accelerated chronic allograft nephropathy (Yilmaz et al, 1996;Kloover et al, 2000).…”

“…However, the pathogenic mechanisms by which HCMV infection contributes to these processes remain to be elucidated. Several studies indicate that vascular injury could result from HCMV-triggered, immunologically mediated processes, in particular in transplant patients (Koskinen et al, 1996;Yilmaz et al, 1996;Lautenschlager et al, 1997b;Martelius et al, 1998;Waldman et al, 1998). Investigations examining the influence of HCMV on immunomodulating molecules on infected cells identified a marked increase in ICAM-1 cellsurface expression as well as mRNA levels in endothelial cells and fibroblasts (Grundy & Downes, 1993;Sedmak et al, 1994;Ito et al, 1995;Burns et al, 1999;Knight et al, 1999Knight et al, , 2000.…”

“…One of the molecular mechanisms underlying the acceleration of vascular disease processes by HCMV infection may be enhancement of transplant immunogenicity. Several studies indicate that this involves the HCMV-induced upregulation of cellular adhesion molecules, which augments the adherance and infiltration of inflammatory cells that are capable of promoting vascular disease (Einsele et al, 1994;Lemstrom et al, 1995;Steinhoff et al, 1995;Koskinen et al, 1996;Yilmaz et al, 1996; Martelius et al, 1998;Waldman et al, 1998;Lautenschlager et al, 1999;The et al, 2001). For instance, cell culture experiments have demonstrated that HCMV-infection of endothelial cells as well as fibroblasts leads to increased cell-surface expression of intercellular adhesion molecule-1 (ICAM-1, CD54) (Sedmak et al, 1994;Grundy & Downes, 1993;Ito et al, 1995;Knight et al, 1999).…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…Upregulation of adhesion molecules on infected ECs may facilitate attachment of monocytes and neutrophils via ELAM1 antigen and could contribute to graft injury (166). Similar increases in ICAM1 have been observed in vivo in CMV-infected renal allografts, in which enhanced chronic kidney allograft rejection is linked to ICAM1 (167). CMV infection of mice in vivo or ECs in vitro induces IL-6 production and activates MCP-1, further increasing inflammation.…”

Implication of γδ T cells in the human immune response to cytomegalovirus

“…CMV infection leads to inflammatory reactions such as severe colitis, retinitis, or pneumonitis (24). In addition, strong evidence has been provided that CMV may be involved in the development of allograft glomerulopathy and chronic rejection in organ transplant recipients (25)(26)(27), although the mechanisms underlying this association remain elusive.…”