Treatment of Extrahepatic Biliary Atresia with Interferon-α in a Murine Infectious Model

Abstract

The etiology of extrahepatic biliary atresia (EHBA) in newborns remains unknown, although a first infectious animal model with complete obstruction of the common bile duct could be established. Intraperitoneal inoculation of newborn Balb/c mice with rhesus rotavirus induced cholestasis, leading, in most cases, to biliary atresia with lethal outcome, similar to EHBA in human newborns. The influence of interferon-alpha (IFN-alpha) on the hepatotropism of rotavirus infection was investigated in this animal model. Single-dose therapy with 10000 IU of IFN-alpha protected all rhesus rotavirus-infected pups from cholestatic disease. The same dose, injected 5 d after infection, had no protective effect. Starting with onset of cholestatic symptoms, the treatment with 10000 IU of IFN-alpha daily showed good results in 29 mice. Seventy-six percent of the mice recovered after 1 wk of therapy. Histologic investigation revealed normal findings in the hepatobiliary tract of clinically normal mice. Twenty-one percent of the descendants of infected and prophylactic IFN-alpha-treated mice showed cholestatic symptoms after infection with rhesus rotavirus (79% in an untreated control group) and a milder form of the illness. In conclusion, we found that prophylactic treatment with IFN-alpha prevented the hepatobiliary system of newborn Balb/c mice from severe damage by rhesus rotavirus in this artificially designed infectious model for EHBA. Infected and icteric mice, treated for 1 wk with IFN-alpha, had good prospects for recovery and prevention of complete and irreversible occlusion of the extrahepatic bile ducts. Infected and prophylactic IFN-alpha-treated dams gave good protection to their descendants. This means that EHBA in this model could probably be averted by maternal antibodies against rotavirus.

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

“…However, it should be noted that there was no significant difference in virus load in the livers and brains of IFN-receptor deficient mice with and without biliary atresia. This observation that is in line with previous studies in Balb/c-mice demonstrating that BA-development is triggered by RRV, but is not correlated to the virus load in the liver (10). Therefore it appears that the interferon type I system plays an important role in the development of BA, rather than just improving the defense against the viral infection, i.e., reducing the virus load.…”

“…This experimental data corresponds to the up-regulation of interferon gamma in the portal ducts of patients with BA (9). The crucial role of interferon is further supported by our previous finding that timely treatment of infected mice with interferon alpha significantly decreases the incidence of BA (10). Therefore, the effects of interferon alpha and gamma appear to be contrary in our model.…”

“…All pups which were infected with virus presented with the oily fur syndrome regardless of the development of BA. This phenomenon is well-known to appear in mice, treated with artificially high doses of rotavirus (6,10,14).…”

“…Newborn mice were infected with 20 L of a suspension containing 10 6 pfu virus at approximately 24 h post partum. Initial experiments were performed using an intraperitoneal application of the virus.…”

“…Readings of the titers was carried out after 4 d of incubation under standard cell culture conditions (Heraeus incubator, EK/5060/CO 2 , 5% CO 2 ). Titers were expressed as plaque forming units (pfu/mL) (10,11).…”