Immunological Gap in the Infectious Animal Model for Biliary Atresia

Czech-Schmidt, Gerard; Verhagen, Willem; Szavay, Philipp; Leonhardt, Johannes; Petersen, Claus

doi:10.1006/jsre.2001.6234

Cited by 91 publications

(107 citation statements)

References 22 publications

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“…The murine model of BA in neonatal mice infected with rhesus rotavirus (RRV) has been used to study the pathogenesis of the disease (2,3). In our early studies using this model, we demonstrated increased mRNA expression of the matrix metalloproteinases (MMPs) in liver tissue samples of infected mice (4).…”

Section: Introductionmentioning

confidence: 97%

“…In our early studies using this model, we demonstrated increased mRNA expression of the matrix metalloproteinases (MMPs) in liver tissue samples of infected mice (4). We had initially suspected that these genes may be upregulated via the transforming growth factor (TGF)β pathway, as we had also seen perturbations in mRNA expression of tissue inhibitor of metalloproteinases (TIMP) Tatiana Iordanskaia, 1 Miroslav Malesevic,2 Gunter Fischer, 3 Tatiana Pushkarsky, 4 Michael Bukrinsky, 4 and Evan P Nadler 1 as well as plasminogen activator inhibitor-1 (PAI-1), which are all regulated by TGFβ. However, several experiments utilizing anti-TGF strategies, comprised mainly of antibody blockade of TGF and its pathway members, failed to demonstrate any effect in this animal model (data not shown).…”

Section: Introductionmentioning

confidence: 99%

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Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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“…That study demonstrated that the portal tract inflammation which was unique to BA was composed of a CD4 + Th1 cell predominant process, characterized by an infiltrate of CD4 + and CD8 + T cells and macrophages with local cellular production of IL-2, IFN-γ and TNF-α. In order to better understand the kinetics of the pathologic immune events in BA, we are utilizing the rotavirus-induced murine model of BA [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…In the Rhesus group A rotavirus (RRV) murine model of BA, newborn mice are infected with RRV in the first day of life which leads to progressive inflammation and obstruction of the extrahepatic bile duct by 2 weeks of age, closely mimicking the lesion in human BA [12][13][14][15]. Furthermore, in the original description of this model, it was noted that the virus was no longer detectable in the liver 2 weeks after infection, yet the inflammatory process was progressive and the mice died of liver failure by 1 month of age [12].…”

Section: Introductionmentioning

confidence: 99%

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia

Mack

Tucker

Sokol

et al. 2005

Clinical Immunology

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Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4 + T cells producing IFN-γ and in macrophages producing TNF-α. The intrahepatic pattern of inflammation evolved rapidly from an initial predominant CD4 + Th1 cellular response to a subsequent influx of activated macrophages producing TNF-α and iNOS. This immune response persisted despite viral clearance and was representative of the hepatic immune profile present in human BA. Utilization of the murine model of BA yielded mechanistic data that can provide much needed insight into the role played by different arms of the immune system related to the pathogenesis of human BA.

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“…The second type of evidence is the murine model of inflammatory cholangiopathy in which newborn mice injected with rhesus rotavirus (RRV) develop extrahepatic biliary obstruction and death (28). This model shares many similarities to the disease process found in children affected with EHBA, including a histologic pattern of inflammatory cell infiltrate found in the portal tract associated with bile duct injury, a gross morphological pattern of extrahepatic bile duct destruction (25), and a temporal dependence with respect to the timing of the inoculation and the resulting induction of biliary obstruction (6). Although this evidence suggests a viral role in the etiology of biliary atresia, the mechanism by which a specific virus causes biliary atresia has not been established.…”

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confidence: 99%

Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

Allen¹,

Jafri²,

Donnelly³

et al. 2007

J Virol

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Biliary atresia is a devastating disorder of the newborn in which afflicted infants develop inflammation and fibrosis of the extrahepatic biliary tract, resulting in cirrhosis and end-stage liver disease. Infection with a virus is thought to be a contributing factor in the etiology of biliary atresia. In the murine model of biliary atresia, perinatal exposure to rhesus rotavirus (RRV) results in biliary epithelial cell infection causing bile duct obstruction. The purpose of this study was to determine if tropism for the biliary epithelial cell was unique to RRV. Newborn mice underwent intraperitoneal injection with five strains of rotavirus: RRV (simian), SA11-FM (simian/bovine), SA11-SM (simian), EDIM (murine), and Wa (human). RRV and SA11-FM caused clinical manifestations of bile duct obstruction and high mortality. SA11-SM caused clinical signs of hepatobiliary injury but the mortality was markedly reduced. EDIM and Wa caused no sign of hepatobiliary disease. The systemic and temporal distribution of viral protein and live virus varied according to the injected strain. Immunohistochemistry revealed that RRV and SA11-FM targeted the biliary epithelial cells. In contrast, SA11-SM was found in the liver but in not in the biliary epithelium. These results indicate that strain-specific characteristics dictate tropism for cells of hepatobiliary origin which in turn impact the ability to induce the murine model of biliary atresia.

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Immunological Gap in the Infectious Animal Model for Biliary Atresia

Cited by 91 publications

References 22 publications

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia

Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

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