February 23, 2010 | 1
"We needed a human liver in a mouse as a tool to study hepatitis B and C viruses, which are totally human hepatotropic—meaning they only infect human cells," explained Inder Verma, senior author of the study published February 22 in the Journal of Clinical Investigation. "It would be nice if we could study hepatitis in a culture dish, but unfortunately [liver cells] lose their properties in vitro."
In 2007, the team published a study in Proceedings of the National Academy of Sciences that showed they could replace some of a mouse’s liver cells with human hepatocytes. The present study went one step further—they could replace enough cells to cause widespread hepatitis (inflammation of the liver) after exposure to the virus. They also showed that conventional antiviral drugs could help clear the hepatitis infection in the chimeric mice.
The researchers say the model will allow them to screen new antiviral therapies. "The current state-of-the-art treatment for hepatitis C is pegylated interferon and ribaviron, which has a success rate of 40-80 percent," says the study’s lead author Karl-Dimiter Bissig. He adds that the prevalence of resistant genotypes in the U.S. brings the success rate closer to 50 percent. "There are a lot of patients that retain the virus after therapy," he says. Furthermore, the therapy is very long and painful, often making patients ill throughout the six-month treatment. "There is room for more effective therapies that are better tolerated by patients. We can use this model for preclinical assessment of potential drugs," he says.
The most serious consequence of hepatitis B and C infection in humans is liver cancer. But unlike humans, the infected chimeric mice showed no signs of cancer despite being particularly susceptible to tumor formation because of the immunosuppression that allowed them to accept the human cell transplant. "We thought we would see tumors because they’re immunosuppressed, but we didn’t," says Verma. "In humans it takes years to develop carcinoma," he says, explaining that perhaps the two-year lifespan of the mouse isn’t long enough to see these effects.
The team plans to soon use the model to see whether they can generate organs using transplanted embryonic and induced pluripotent stem cells rather than mature liver cells. They will also collaborate with researchers at the University of California in San Diego to study other pathogens that require a human host, such as malaria.