A rat model of monitoring liver allograft rejection

Martelius, Timi; Mäkisalo, Heikki; Höckerstedt, K; Taskinen, Eero; Lautenschlager, Irmeli

doi:10.1111/j.1432-2277.1997.tb00549.x

Cited by 12 publications

(11 citation statements)

References 19 publications

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“…We previously developed a rat model of acute liver allograft rejection that showed an intense inflammatory infiltrate in the portal areas 1 week postoperatively and developed relatively slowly into macrophage reaction, graft necrosis, and fibrosis within 36 Ϯ 20 days. 15 In this study, special attention was paid to the effect of CMV infection on the inflammatory response of rejection and histological alterations of the bile ducts and vascular structures of the liver graft. …”

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confidence: 99%

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

et al. 1998

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It has been suggested that cytomegalovirus (CMV) infection is involved in allograft rejection. In liver transplantation, it has been suggested that CMV is associated with the development of vanishing bile duct syndrome (VBDS), and persistent CMV has been found in liver grafts that develop chronic rejection. In this experimental study, the effect of rat CMV (RCMV) infection on intragraft changes was investigated in a rat model of acute liver allograft rejection. Liver transplantations were performed in a rat strain combination of PVG (RT1 c ) = BN (RT1 n ). No immunosuppression was given. One group of animals was infected with RCMV Maastricht Strain (10 5 plaque-forming units, intraperitoneally), and another group was left uninfected. The grafts were examined histologically after the rats were killed on postoperative days 7 through 9 at the early phase and days 20 through 30 at the late phase of rejection. Immunohistochemical studies were performed to demonstrate the immunological activation markers major histocompatibility complex class II and interleukin 2 receptors, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their ligands. RCMV infection was demonstrated from the grafts by culture and direct antigen detection. In liver allografts undergoing acute rejection, CMV significantly increased portal inflammation and caused more severe bile duct damage than in the uninfected grafts. CMV was also linked to the induction of VCAM-1 in the endothelial cells. The ongoing infection was found to vary over time in the different structures of the liver grafts, including the vascular endothelium and bile ducts. Our results support an association between CMV infection and the immunological mechanisms of rejection, as well as the role of CMV in the development of bile duct damage in liver allografts. (HEPATOLOGY 1998;27;996-1002.)Cytomegalovirus (CMV) infection is a major source of morbidity and mortality in transplant recipients and other immunocompromised patients. The incidence of CMV infection among liver transplant recipients is high, and 40% to 70% of these patients develop a symptomatic CMV disease. 1-4 A variety of clinical manifestations of CMV infection, such as fever, pneumonitis, gastroenteritis, and hepatitis, have been described. The liver is a privileged site for CMV, and the liver graft has been found to be the most commonly affected organ in primary CMV infections. 1 CMV has also been suggested to be linked to organ allograft rejection in both kidney and heart transplantation. [5][6][7] In liver transplantation, the importance of concomitant CMV infection during late acute rejections has been reported. 8 An association between CMV and vanishing bile duct syndrome (VBDS) in hepatic allografts has been found, 9 and persistence of CMV DNA in hepatocytes, 10,11 bile ducts, and vascular structures 11 of the liver has been demonstrated in patients with VBDS. We recently showed that persistent CMV infection in liver allografts is associated with chronic rejection. 11 Va...

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confidence: 99%

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

et al. 1998

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“…No immunosuppressive drugs were given to any of the animals. We have previously demonstrated that, in this strain combination, liver allotransplantation results in prolonged acute rejection with an intense peak of lymphoid activation at 1 week after transplantation, leading to later macrophage-dominated response and advanced tissue damage at a mean survival time of 37 days [12]. Grafts were harvested at 1 week (n = 5 in the CMV group, n = 3 in the uninfected group) and at 4 weeks (n = 6 per group) so that we could observe both the peak of rejection and the more prolonged phase.…”

Section: Transplantation and The Rejection Modelmentioning

confidence: 92%

“…In this rat model of liver transplantation, there are intense signs of acute rejection at 1 week, with portal inflammation and endotheliitis in the graft. In the later phase, at 4 weeks, there is still portal inflammation, but clearly less than at the peak, and the histological pattern is that of necrosis, fibrosis, and bile duct proliferation in response to injury [12], CMV infection significantly increased portal inflammation and bile duct damage in the late phase [13].…”

Section: Statisticsmentioning

confidence: 98%

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

Martelius¹,

Wolff²,

Bruggeman³

et al. 2002

Transplant International

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Cytomegalovirus (CMV)Keywords Cyclo-oxygenase-2 .infection has been shown to increase inflammation in rat liver allografts. In-vitro CMV has been shown to transactivate cyclo-oxygenase-2 (COX-2), while COX-2 plays a role in the CMV replication cycle. Our aim was to investigate the expression of COX-2 in liver allograft rejection and concomitant CMV infection. Expression of COX-2 was studied immunohistologically in rat liver allografts with or without rat CMV infection, in isografts, and in normal rat liver. There were small amounts of COX-2-positive mononuclear inflammatory cells in the normal liver and isografts. Acute rejection increased the amount of COX-2-expressing cells in the portal areas only, whereas concomitant CMV infection did this also in the sinusoid area. COX-2 may play a role in CMV infection in vivo as well. The possible role of COX-2 in the association between CMV infection and allograft rejection warrants further study. Liver rejection . Cytomegalovirus

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“…12 BN to BN syngeneic transplantations were performed for syngeneic controls. The rats were fed with regular rat food and tap water ad libitum.…”

Section: Ratsmentioning

confidence: 99%

“…11 We have previously characterized the rejection response in a rat liver transplantation model with a donor-recipient strain combination of PVG(RT1 c ) into BN(RT1 n ). 12 We wanted to study whether VAP-1 expression would be induced in acute liver allograft rejection. We have also previously shown that rat CMV (RCMV) increases inflammation, bile duct destruction ,and sinusoidal VCAM-1 expression in rat liver allografts with concomitant rejection.…”

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Induction of Vascular Adhesion Protein-1 during Liver Allograft Rejection and Concomitant Cytomegalovirus Infection in Rats

Martelius¹,

Salmi²,

Wu³

et al. 2000

The American Journal of Pathology

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Vascular adhesion protein-1 (VAP-1) is an adhesion molecule controlling lymphocyte recirculation through high endothelial venules of the lymph nodes. It has also been shown to be induced and to mediate lymphocyte adhesion at sites of inflammation. We studied the expression of VAP-1 and two other inducible adhesion molecules ICAM-1 and VCAM-1 in our experimental model of rat liver allograft rejection and, in addition, the effect of concomitant rat cytomegalovirus (RCMV) infection on this expression. Expression of VAP-1, ICAM-1, and VCAM-1 was studied in rat liver allografts with or without RCMV infection, isografts, and normal rat liver. Immunoperoxidase technique and monoclonal antibodies including a novel anti-VAP-1 reagent were used. VAP-1 expression was induced by acute rejection in sinusoids, hepatocytes, and also in bile ducts, when compared to the isografts or normal liver, where only blood vessels were consistently positive. Sinusoidal and hepatocyte expression of VAP-1 was prolonged by the presence of RCMV. ICAM-1 and VCAM-1 expression was also induced by acute rejection. However, RCMV increased sinusoidal VCAM-1 expression compared to uninfected grafts. The present experimental study shows that VAP-1 is up-regulated in acute rejection of liver allografts, and that this up-regulation is prolonged by RCMV infection. The hallmark of rejection is the influx of inflammatory cells, mainly lymphocytes and monocytes/macrophages into the graft. This process involves sequential adhesive interactions between the leukocyte and the endothelium. Initial physiological rolling is followed by reversible and then firm adhesion when endothelial activation by inflammatory cytokines and leukocyte activation by the interaction with activated endothelium and/or chemokines take place. The complex process of adhesion and diapedesis of leukocytes into the tissue sites of inflammation is coordinated by several adhesion molecules.

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A rat model of monitoring liver allograft rejection

Cited by 12 publications

References 19 publications

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts

Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat

Induction of Vascular Adhesion Protein-1 during Liver Allograft Rejection and Concomitant Cytomegalovirus Infection in Rats

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