Yilmaz S, Koskinen P K, Kallio E, Bruggeman C A, Häyry P J, Lemström K B
Transplantation Laboratory, University of Helsinki, Finland.
Kidney Int. 1996 Aug;50(2):526-37. doi: 10.1038/ki.1996.345.
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.
在人类肾移植中，已证实急性排斥反应和肾小球病与巨细胞病毒（CMV）感染有关。为了研究CMV感染对实验性慢性肾移植排斥反应发展的影响，采用了从DA（Ag - B4，RT1a1）大鼠供体到WF（Ag - B2，RT1u）大鼠受体的异位肾移植。动物接受皮下注射环孢素A（CsA）5 mg/kg/天，持续1周或12周。两组受体感染10⁵个大鼠CMV（RCMV）空斑形成单位，另外两组不感染作为对照。移植后12周取出移植物进行组织学和免疫组织化学检查。RCMV感染显著增强了持续使用CsA的大鼠慢性肾移植排斥反应的发展，包括间质炎症强度（P < 0.025），特别是炎性浸润中嗜派洛宁细胞的程度（P < 0.025）、肾小球系膜基质增加（P < 0.05）和毛细血管基底膜增厚（P < 0.01）、移植物血管内皮细胞肿胀程度（P < 0.025）和内膜增殖程度（P < 0.025），以及肾小管上皮萎缩程度（P < 0.025）。慢性移植损伤指数（CADI）在RCMV感染的移植物中显著增加至4.3 ± 0.8，而未感染的为0.8 ± 0.4（P < 0.02）。此外，RCMV感染显著增加了急性排斥反应发作的次数（血清肌酐> 200 μmol/升，P < 0.05），并使终末期血清肌酐几乎增加了一倍。RCMV感染显著增加了血管内皮细胞（P < 0.05）和肾小管上皮细胞（P < 0.01）上ICAM - 1的表达，并与间质、肾小球和肾小管炎症增强有关。在持续使用CsA的所有移植物中，80%在感染后1周可在散在的炎性细胞中观察到RCMV抗原，12周时在肾小管上皮细胞中观察到。在1周时停用CsA的严重炎症移植物中，未证明RCMV感染对慢性肾移植排斥反应所致组织学变化有增强作用。我们的结果表明，在CsA免疫抑制期间，RCMV感染增强了慢性肾移植排斥反应，伴有间质炎症增加以及血管内皮和肾小管上皮ICAM - 1表达增加。
