To avoid killing mouse liver cells too early (or killing the mice entirely), Bissig’s team administered a drug that blocks the toxic byproducts of tyrosine buildup from killing liver cells. By putting the mice on the drug, and taking them off the drug a little at a time, researchers found that they could control the rate at which rodent liver cells died off.
The team then injected mice with hepatocytes from various human donors, and found that the cells were able to take over 97 percent of the mouse liver. The “humanized” mice were then infected with hepatitis B and C, and researchers found high levels of the virus in the bloodstream–versus normal mice, which are impervious to the disease and are able to clear the virus out quickly.
Bissig and his colleagues went a step further and treated the infected mice with a drug typically used to treat humans with hepatitis C. They found that, after treatment, the mice exhibited a thousand-fold decrease in viral concentration in the blood, similar to drug reactions in human patients.
Charles Rice, who heads the laboratory for virology and infectious disease at Rockefeller University, says the new chimeric model is a robust improvement over existing study models for viral hepatitis. Further improvements, Rice explains, could include engineering human cell types, other than hepatocytes, that also appear in the human liver. While the majority of the human liver is composed of hepatocytes, there are a few other cell types that may interact with hepatocytes and affect how a virus infects the liver. Engineering other liver cells could more accurately depict a working human liver and its response to disease.
Raymond Chung, associate professor of medicine at Harvard Medical School, suggests another improvement in designing an accurate mouse/human liver: to engineer a mouse with a human immune system. “This is still not an ideal model,” says Chung of Bissig’s research. “You can’t necessarily accurately evaluate antiviral drugs given the lack of adaptive immune response in these animals.”
Bissig says that in the future, he and his team hope to add a human immune system to their mouse model, so they can see how hepatitis acts, not only in a human liver, but in the presence of a normal, healthy human immune system.