The work holds promise for understanding the mechanisms of disease and for drug discovery
Researchers at Jefferson Medical College have developed the first mouse model of chronic liver disease caused by hepatitis B virus (HBV), which promises to accelerate the discovery of drugs against the disease. Such a model may provide a better understanding of how HBV actually causes liver disease.
Mark A. Feitelson, Ph.D., professor of pathology, anatomy and cell biology at Thomas Jefferson University in Philadelphia and his colleagues there developed transgenic mice that are chronic carriers of HBV. These mice were made by introducing the HBV genetic information into mouse eggs, and breeding mice that had viral DNA in all of their cells. Such mice consistently replicate HBV, which is detected in their blood, throughout their lives. Although other similar models have been made using normal mice, none develop chronic liver disease because the immune system sees the virus as "self" during embryonic development.
To solve this problem, Dr. Feitelson used severe combined immunodeficient (SCID) mice as viral hosts. These SCID mice lack critical immune system elements that normally would fight the virus. When the mice are reconstituted with a normal immune system in a procedure akin to bone marrow transplantation, they do not recognize the virus as "self" and develop liver disease.
The researchers report their results in August in the journal Nature Medicine.
"The mice see the virus as foreign, which is what they should do," Dr. Feitelson explains. This is similar to the way the human immune system recognizes HBV shortly after exposure to the virus, he points out.
In addition to chronic liver disease, these mice have also been manipulated to develop acute disease. "The differences between acute and chronic disease in these mice will be key to the development of new approaches against the latter," says Dr. Feitelson, noting that many individuals with acute disease recover.
The mouse model may also have major implications for developing drugs against diseases that remain a major international public health problem. "One of the largest problems in the field of hepatitis B is what to do with carriers at high risk for the development of chronic liver diseases," Dr. Feitelson says. "We have a vaccine to prevent the disease and tests to screen the blood supply, but there are still an estimated 350 million HBV carriers at high risk of developing hepatitis, cirrhosis, and liver cancer." As many as 2 billion people worldwide are infected with the virus, though they are not carriers. Chronic HBV infection is the ninth leading cause of death in the world, accounting for more than 1 million deaths in 1996 alone.
The new model opens up several opportunities for scientists studying HBV. While scientists know that the pathogenesis of chronic hepatitis B is due to immune responses against the virus-infected liver cells, "There are basic science questions of pathogenesis that are unsolved and which can be addressed by this model," Dr. Feitelson says.
The HBV transgenic SCID mouse provides an easily manipulated model for both basic and applied research compared to wild animals, such as woodchucks, ground squirrels and ducks, which are naturally infected with hepatitis B-like viruses.
"We can test drugs in the liver against the virus in the absence of disease – if we don’t reconstitute the immune system," Dr. Feitelson says. "Or we can replace the immune system and then ask what the drug does to the virus and disease."
The model is both powerful and flexible, he says. It will enable scientists to target the liver with viral gene therapy, decide which virus proteins are targets for immunological responses, and identify the parts of the immune system important for targeting the virus.
The model has broad implications for studying the pathogenesis of other selected diseases. "Scientists can use the same approach to study the pathogenesis of immune-mediated diseases against other infectious agents and in selected autoimmune diseases," he explains. "For something that is foreign, you can reconstitute the immune system and look for development of pathology to that foreign protein."
For more information about participating in the clinical trial, please call 1-800-JEFF NOW.
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