Hepatitis C treatment may
lie in body's own immune system
BY KRISTIN WEIDENBACH
It stopped Evel Knievel in
his tracks and threatened to silence David Crosby of the
rock band Crosby, Stills and Nash. But they are only two
of the 4 million Americans struggling to beat hepatitis C
-- a disease affecting the liver, for which there is no
easy treatment, no vaccine and no cure. For most
sufferers, like Knievel and Crosby, a liver transplant is
the only option when the disease progresses unchecked and
the organ ultimately fails.
Researchers at the School
of Medicine may have found the first clue as to how the
body can successfully fight off infection by the
hepatitis C virus. By studying chimpanzees that have
overcome infection naturally -- effectively ridding their
bodies of the viral invaders on their own -- the
researchers have found that it is critical for the cells
of the immune system to wage a broad assault at the
earliest stages of the infection to successfully ward off
the virus.
"Only 15 to 20
percent of people seem capable of terminating hepatitis C
virus infection naturally -- that means at least 80
percent have inadequate defense against it and become
chronically infected," said Stewart Cooper, MD, a
Stanford research fellow and lead author of the study
reported in the April issue of the journal Immunity.
"By uncovering how the body is naturally capable of
fighting off the infection, we now have a rational target
for vaccine development."
Cooper, a research fellow
in the laboratory of Peter Parham, PhD, professor of
structural biology and microbiology and immunology,
studied six chimpanzees infected with hepatitis C. Four
of the animals developed a long-term infection similar to
that seen in humans; however, two of the chimps showed no
signs of the infection beyond three months, indicating
their immune systems had successfully overcome the
infection. One and a half years later, the two
chimpanzees still showed no trace of the virus.
When Cooper and his
colleagues analyzed cytotoxic T-cell lines that had been
taken from the livers of the six animals they discovered
a key difference between the cells of the infected chimps
and those of the disease-free animals. T cells from the
two chimps that had beaten the virus had gone to work
early in the infection, mounting an all-out assault on
the virus. In contrast, T cells from the chimps that
developed chronic hepatitis C showed a delayed response,
with T cells attacking more limited parts of the virus
and utilizing fewer of the body's immunological defense
molecules.
"These results
suggest that unless a certain threshold of T cell
response is achieved during acute hepatitis, infection is
likely to persist," said Cooper.
In addition to discovering
that a certain level of T cell response is required to
fight off the invading infection, the study has helped
identify the importance of a robust T cell response over
an antibody response, at the time of initial infection.
The human immune system
has two major defense systems to combat foreign invaders
-- T cells and B cell-produced antibodies. Different
diseases are brought under control by one of these two
systems. Until now, scientists have not really understood
which part of the immune system is most important in
fighting off infection by the hepatitis C virus. Prior
conventional thinking held that antibodies played an
important role, but the Cooper study suggests that it is
the T cells that are critical in combating the virus.
Knowing which system is paramount in fighting off the
disease is crucial for efforts to develop a vaccine
against it.
"Most of the time
when you study a disease you are looking at individuals
who are already diseased -- the immune system is already
perturbed," said Parham. "With this work, you
can look at individuals before, during and after the
disease. And the chimp model means that you are looking
at animals that are very closely related to humans."
An estimated 8,000 to
10,000 people die each year from hepatitis C. Although
the peak period for new infections in the United States
is believed to have been in the 1960s and '70s, the
disease can silently attack the liver for 10 to 30 years
before an infected individual is even aware that he or
she is harboring the virus. Thus, although the number of
new infections is declining, the number of people
developing serious hepatitis C-induced liver problems is
expected to increase over the coming decades.
About 85 percent of all
people who contract the virus end up with a long-term
infection that can lead to irreversible liver damage and
scarring, and possibly liver cancer. The disease is the
most common reason for liver transplants in the United
States.
Cooper believes that the
threat to public health posed by the hepatitis C virus is
just as important as that of the human immunodeficiency
virus that causes AIDS. Although AIDS is more deadly, the
hepatitis C virus currently affects four times as many
Americans as HIV.
Cooper, Parham and Erin
Adams, a University of California, Berkeley, graduate
student working with the Stanford scientists,
collaborated with Ann Erickson and other researchers from
Chiron Corporation, of Emeryville, Calif., to conduct
their research. Christopher Walker, PhD, formerly of
Chiron and now at Ohio State University, is the senior
author of the scientific report arising from the study.
It was Chiron scientists
who first identified the hepatitis C virus in 1989 -- a
crucial advance that paved the way for the company's 1992
development of a diagnostic test to screen for the
disease. Many carriers of the virus were unwittingly
infected by tainted blood transfusions before the
screening test became available. Researchers have been
searching for treatments since the discovery of the
hepatitis C virus but efforts have been hampered by the
fact that the virus will not grow in liver cells
maintained outside the body. Scientists have also been
limited because the chimpanzee is the only animal model
for the disease, according to Cooper.
Cooper plans to extend his
study to humans. Chimps and humans have almost identical
immune systems and react similarly to the hepatitis C
virus, so he believes that his findings in chimps are
likely to hold true in humans. Like the primates, some
people are known to overcome hepatitis C infection
naturally but since they are soon well, with no lingering
signs of infection, these people are difficult to find
and haven't been studied in detail. As a result of his
animal research, Cooper now has the methods to
retrospectively study the immune responses of people who
have overcome the hepatitis C virus.
The study was supported by
funds from the National Institutes of Health and Chiron
Corporation. Cooper's research is supported by the
American Arthritis Foundation. SR
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