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

Abstract

BackgroundA proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous immunoglobulin (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high dose immunoglobulin (IgG) treatment in the rhesus rotavirus (RRV)-induced mouse model of BA.MethodsNewborn 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.ResultsThere 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 IL-2, IFN-γ and TNF-α and CD8+ T cell production of IFN-γ, as well as increased levels of regulatory T cells.ConclusionsHigh 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.