August 27, 2004

Diverse immune response may help fight hepatitis C

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Shaun Cole, a new Interdisciplinary Graduate Program student, climbs the swinging pole section of the alpine tower at Camp Widjiwagan during orientation activities for graduate students. Photo by Anne Rayner

Diverse immune response may help fight hepatitis C

Scientists may be closer to understanding why about a third of people who are exposed to hepatitis C never get sick.

The answer appears to have something to do with the diversity of the immune response to infection, says Spyros Kalams, M.D., associate professor of Medicine at Vanderbilt University Medical Center.

This information may help researchers design a vaccine to prevent hepatitis C infection, or find other ways to “manipulate” the immune system to better fight off the virus, Kalams says.

In a study in chimpanzees, Kalams and colleagues from the Columbus Children’s Research Institute and Massachusetts General Hospital found that cytotoxic T cells, the white blood cells that normally attack invading pathogens, did not respond to the rapidly mutating hepatitis C virus in animals that developed chronic infection.

In animals that cleared the virus, however, the T-cell response was diverse and robust, the researchers reported in the Aug. 2 issue of the Journal of Experimental Medicine. “The more weapons you’re putting against the virus, the less it’s able to escape,” Kalams concluded.

About 4 million Americans have hepatitis C infection. The virus, which is spread primarily through blood-to-blood and sexual contact, infects the liver. It can cause chronic hepatitis, cirrhosis and liver cancer, resulting in the need for a liver transplant.

Chimpanzees are useful for studying hepatitis C because they are infected with the same strains of the virus that infect humans. They also clear the virus at about the same rate — about 30 percent of the time, Kalams said.

One of Kalams’ colleagues, Christopher Walker, Ph.D., who directs the Center for Vaccines and Immunity at Columbus Children’s Research Institute, isolated clones of T-cells from the livers of chimpanzees infected with hepatitis C.

The chimpanzees were housed at the New Iberia Research Center in Louisiana.

Normally, receptors on the surfaces of cytotoxic T cells recognize and latch onto viral peptides or small protein markers on the surface of cells infected with the virus. In animals that clear infection, a diverse array of T-cell receptors is able to recognize each viral peptide, making it difficult for the virus to mutate and thereby evade detection by the immune system.

“In those cases, the animal not only cleared virus but when you re-challenged it with the same virus, it cleared it even faster,” he said. “Those cells expanded very rapidly and just took care of the infection.”

T-cells isolated from chronically infected animals, however, were notable in the uniformity of their receptors, Kalams says. They did not seem able respond to mutated versions of the virus. It is not known why some animals — and presumably humans — have a more diverse immune response than others.

One possibility, says Kalams, is that at some point the virus takes advantage of the immune system’s “brake” — a population of white blood cells that suppress immune responses in order to keep them from getting out of control.

In this case, however, the virus stimulates the suppressor cells in order to hide from the cytotoxic ones. “And now the virus changes, and you’ve got this environment where you don’t have new (immune) responses generated,” he said.

The study was led by Dirk Meyer-Olson, M.D., Ph.D., a former fellow at Massachusetts General Hospital, who now is at Hanover Medical School in Germany.

Other contributors were Naglaa H. Shoukry, Ph.D., at the Columbia Children’s Research Institute; Helen Kim, Douglas P. Olson and Kelly Hartman at Massachusetts General Hospital; and Kristen W. Brady and Ayumi K. Shintani at Vanderbilt.

People infected with HIV sought for Vanderbilt study

A diverse immune response also may aid in the fight against the human immunodeficiency virus (HIV), which cases AIDS.

Spyros Kalams, M.D., has been researching “long-term non-progressors,” people who develop AIDS symptoms relatively slowly after infection. He would like to compare their immune systems to people who have recently “sero-converted,” or produced antibodies against HIV – an indication of early infection.

“We’d really like to follow acutely infected patients to see how their immune response evolves in relation to the virus,” says Kalams, an expert in “viral immunology,” the body’s response to viral infections. “We’re working on the hypothesis that our long-term non-progressors are going to have diverse T-cell (responses).”

If confirmed, measuring how potential vaccines affect the diversity of the immune response could become a valuable way to gauge their effectiveness, he says.

For more information about this study or to volunteer, contact Susan Montgomery, R.N., research clinical specialist, at 467-0154, ext. 120.