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High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.

ABSTRACT: A proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous Ig (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high-dose IgG treatment in the rhesus rotavirus (RRV)-induced mouse model of BA.Newborn mice were infected with RRV, and jaundiced mice were given high-dose IgG or albumin control. Survival, histology, direct bilirubin, liver immune cell subsets, and cytokine production were analyzed.There was no difference in overall survival between RRV-infected groups, however high-dose IgG resulted in decreased bilirubin, bile duct inflammation, and increased extrahepatic bile duct patency. High-dose IgG decreased vascular cell adhesion molecule-1, resulting in limited migration of immune cells to portal tracts. High-dose IgG significantly decreased CD4(+) T cell production of interleukin (IL)-2, interferon (IFN)-?, and tumor necrosis factor (TNF)-? and CD8(+) T cell production of IFN-?, as well as increased levels of regulatory T cells.High-dose IgG therapy in murine BA dramatically decreased Th1 cell-mediated inflammation and biliary obstruction. This study lends support for consideration of IVIg clinical trials in infants with BA, to diminish the progressive intrahepatic bile duct injury.

SUBMITTER: Fenner EK

PROVIDER: S-EPMC4062601 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.

Fenner Erika K EK Boguniewicz Juri J Tucker Rebecca M RM Sokol Ronald J RJ Mack Cara L CL

Pediatric research 20140411 1

<h4>Background</h4>A proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous Ig (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high-dose IgG treatment in the rhesus rotavirus (RRV)-induced mouse model of BA.<h4>Methods</h4>Newborn mice were infected with RRV, and jaundiced mice were given high-dose IgG or albumin control. S ...[more]

PMID: 24727948

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Project description:Background & aimsBiliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to the virally induced mechanism of disease, the role of inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption of the inflammasome suppresses the neonatal proinflammatory response and prevents experimental BA.MethodsWe determined the expression of key inflammasome-related genes in livers from infants at diagnosis of BA and in extrahepatic bile ducts (EHBDs) of neonatal mice after infection with rotavirus (RRV) immediately after birth. Then, we determined the impact of the wholesale inactivation of the genes encoding IL-1R1 (Il1r1-/-), NLRP3 (Nlrp3-/-) or caspase-1 (Casp1-/-) on epithelial injury and bile duct obstruction.ResultsIL1R1, NLRP3 and CASP1 mRNA increased significantly in human livers at the time of diagnosis, and in EHBDs of RRV-infected mice. In Il1r1-/- mice, the epithelial injury of EHBDs induced by RRV was suppressed, with dendritic cells unable to activate natural killer cells. A similar protection was observed in Nlrp3-/- mice, with decreased injury and inflammation of livers and EHBDs. Long-term survival was also improved. In contrast, the inactivation of the Casp1 gene had no impact on tissue injury, and all mice died. Tissue analyses in Il1r1-/- and Nlrp3-/- mice showed decreased populations of dendritic cells and natural killer cells and suppressed expression of type-1 cytokines and chemokines.ConclusionsGenes of the inflammasome are overexpressed at diagnosis of BA in humans and in the BA mouse model. In the experimental model, the targeted loss of IL-1R1 or NLRP3, but not of caspase-1, protected neonatal mice against RRV-induced bile duct obstruction.Lay summaryBiliary atresia is a severe inflammatory and obstructive disease of bile ducts occurring in infancy. Although the cause is unknown, activation of the innate and adaptive immune systems injures the bile duct epithelium. In this study we found that patients' livers had increased expression of inflammasome genes. Using mice engineered to inactivate individual inflammasome genes, the epithelial injury and bile duct obstruction were prevented by the loss of Il1r1 or Nlrp3, with a decreased activation of natural killer cells and expression of cytokines and chemokines. In contrast, the loss of Casp1 did not change the disease phenotype. Combined, the findings point to a differential role of inflammasome gene products in the pathogenic mechanisms of biliary atresia.

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High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.

Publications

High-dose IgG therapy mitigates bile duct-targeted inflammation and obstruction in a mouse model of biliary atresia.

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