New molecular signature detected for common cause of pediatric liver disease

The unexpected discovery of a new molecular signature for biliary atresia may lead to a new therapeutic target for this frequently lethal condition.

Researchers from Cincinnati Children’s report in the November issue of the Journal of Clinical Investigation that not all children with biliary atresia share the same disease process. Some patients have a second molecular conductor of disease called Th2 (T helper cell 2) immune system.

Biliary atresia is the most common cause of severe pediatric liver disease. Driven by an overly aggressive immune system response after birth, the condition destroys the bile ducts in and near the liver in the first few months of life. Even with treatment, children often need a liver transplant within two years of birth.

New dimension to biliary atresia

Progress in finding better therapies has been hampered by a limited knowledge of biological processes driving the disease, says Jorge Bezerra, MD, principal study investigator and a member of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s.  

“Our findings add a new dimension to the understanding of biliary atresia,” Bezerra says. “They provide a potential target for new therapies and have implications for clinical trials. Now, depending on the molecular signature of a child’s disease, we can develop new strategies to also target the Th2 immune system with anti-inflammatory agents.”

Previous clinical trials have shown that not all children with biliary atresia respond in similar fashion to treatment. The new study may help explain why, Bezerra says.

Mouse model reveals Th2 link

Until now, only molecular signals from the Th1 cytokines had been linked consistently to the biochemical processes that cause biliary injury. In biliary atresia, these cytokines cause the immune system to go into overdrive, piling on damage to the bile ducts and the liver.

However, some biliary atresia patients exhibit low levels of Th1. This led Bezerra and his colleagues to look for other factors.

The study involved testing mice genetically modified to lack a Th-1 response. When exposed to a rotavirus, these mice generated an almost immediate and robust immune response involving Th2 cytokines.

Bile duct damage and obstructions occurred within seven days. The researchers then demonstrated that Interleukin 13 (IL-13) reduced tissue infiltration by immune cells and helped maintain bile duct integrity.

Results linked to children

Then Bezerra examined the blood of children with biliary atresia and found that some of them exhibit high levels of Th2 cytokines. This, coupled with the current study findings, demonstrate “a compatibility between Th2 and the onset of biliary atresia, and suggest that patient subgrouping in future clinical trials should account for differences in Th2 status,” he says.

The Th2 study was funded in part by grants from the National Institutes of Health and the Digestive Disease Research Core Center in Cincinnati.  It follows a study from Bezerra and colleagues published Sept. 28, 2011, in Science Translational Medicine, which points to how immune system dendritic cells trigger the initial immune response in a mouse model of biliary atresia.