Progress in Developing Animal Models for Biliary Atresia

Abstract

Animal models for extrahepatic biliary atresia (EHBA) have failed to simulate the course of the disease. Until now only a few aspects of the entity could be investigated and no model was helpful in discovering the etiology of EHBA. Following the suspicion of a viral and hepatotropic infection, investigations in an infectious mouse model were continued. The results of previous and topical studies are summarized here. Infection of newborn Balb/c-mice with rhesus rotavirus (RRV) leads to cholestasis in 85% of the animals followed by a lethality of 90%. Preparation and histomorphological investigation of liver and ligamentum duodenale reveal EHBA of varying extent. Clinical course and morphological findings in mice are very similar to EHBA in newborn children and the results are presented in a chronological table. Hepatobiliary morbidity and lethality after RRV infection is higher in Balb/c-mice than in other mouse strains. This observation supports the suspicion that immunocompetence might be a determining factor in the etiology of EHBA. Initial therapeutic trials were made using this model by treating infected newborn mice with interferon-alpha (IFN). The prophylactic application of IFN protects the infected mice from cholestatic symptoms and appears to induce partial immunity. Their descendants are protected against the hepatotropic effect of RRV infection. Infected animals presenting with clinical signs of cholestasis can be treated successfully by IFN-therapy for one week. In the presented animal model. EHBA can be better induced and simulated than by any other method. As a first trial, a non-surgical and more etiologically orientated therapeutic method is tested in this model.

Effect of Rotavirus Strain on the Murine Model of Biliary Atresia

“…1C) for pups injected with RRV. These findings were consistent with previous reports in which the murine model of biliary atresia was established (24)(25)(26)28).…”

“…Consistent with reports in which the model was established (24)(25)(26)28), newborn mice injected with RRV developed the murine model of biliary atresia with the clinical manifestations of jaundice, acholic stools, and bilirubinuria. Cholangiography revealed bile duct obstruction.…”

Type-I But Not Type-II Interferon Receptor Knockout Mice Are Susceptible to Biliary Atresia

“…In the present study, newborn mice of the IFN-mutant strains and its wild type were more susceptible to RRV than other inbred mouse strains (19). High lethality occurred in the pups which were intraperitonally infected within their first week of life and none of these mice survived to develop biliary atresia.…”

“…These findings raised the question of potential autoimmunological co-mechanisms (17) and Perlmutter finally, proposed that BA, rather than being a single disease could represent a common feature initiated by a variety of different etiologic factors (18). To investigate the etiology of BA we developed a mouse model of biliary atresia based on observations of M. Riepenhoff Talty (6,14,19).…”

Corticosteroid treatment in biliary atresia: Tonic or toast?

“…6 A similar T helper 1 response is replicated in the most promising animal model of BA, the rhesus rotavirus-infected newborn mouse model. [7][8][9] The innate immune response is also activated in the human BA liver, as demonstrated by the later appearance of cells of the CD68ϩ macrophage/ monocyte family in portal tracts and evidence of chemokine and cytokine release by these and related cells. 7 Abnormal expression of cellular adhesion molecules (intercellular cell adhesion molecule, CD54, vascular cell adhesion molecule, CD62E) on biliary epithelium and vascular endothelium and elevated circulating levels of soluble adhesion molecules have also been observed.…”