New Immune Theory
CVNW83A at prodigy.com
Mon Apr 10 22:08:28 EST 1995
I found this short piece in the prestigious journal "Business Week." I
don't know enough immunology to be much of a judge, but a draft paper Dr.
Matzinger sent me explains her ideas in more detail, using tissue
transplantation and tumors as examples. Finding the exact nature of
Matzinger's "alarm signal" that triggers the immune response could be
the foundation for broad and really productive medical research &
"STANDING IMMUNE-SYSTEM THEORY ON ITS HEAD"
Most researchers think the immune system springs into action when
it encounters a foreign substance. This discrimination--between "self"
and "non-self" has been the central metaphor of immunology since the
The trouble is, it's wrong. says National Institutes of Health
researcher Polly Matzinger. Last April, the 47-year-old head of the T-
Cell Tolerance & Memory section at the NIH's National Institute of
Allergy & Infectious Diseases proposed a different metaphor. What
spurs the immune system, Matzinger says, is a shout of "danger" from
cells dying in distress.
Matzinger argues that T-cells--the foot soldiers in the battle
against cancer--don't care much if the antigens they encounter are
foreign or "self." She like other researchers, notes that T-cells
require a signal from a critical white blood cell, called a dendritic
cell, before they load their weapons and fire. Dendritic cells inhabit
every tissue of the body, but they mostly lie dormant.
To wake them up, cells nearby must call out in shock. "This
[alert] is the initiation'" Matzinger declared at a recent Cancer
Research Institute seminar in New York. "Without it, you don't get an
immune response. Ever."
To colleagues, Matzinger's theory has been a wake-up call. "It's
a provocative point of view that will influence many people to
reexamine their work," says William E. Paul, head of NIH's Office of AIDS
Research. It has already sparked heated discussions at immunology
meetings and swayed some pioneers in the field.
Kevin Lafferty, director of the John Curtin School of Medical
Research in Camberra, Australia, says he resisted the idea from the first.
Then Lafferty started to do some hard thinking about his own results in
animal tissue transplantation. If he removed dendritic cells from a
piece of skin and transplanted it to another animal, the graft would
take he says, even though the tissue was foreign. "My whole work was
showing that the 'self/non-self' metaphor was wrong."
Matzinger, who spends as much as 18 hours a day in the lab and
devotes her scant spare time to raising sheepdogs, (actually TRAINING
border collies AS sheepdogs) says she already had doubts about the "self"
metaphor as a graduate student. She was perplexed that T-cells don't
attack "foreign-looking" substances that appear after puberty, such as
milk proteins from newly lactating breasts.
Years later, at the NIH, a young oncologist named Ephraim J.
Fuchs expressed similar doubts. "We knew the alert signal had to be
danger," Matzinger recalls. "Then one day, in the bath, I realized it
was caused by distressed cell death." The theory's implications go
beyond cancer vaccines. Matzinger says immunosuppressive drugs such as
cyclosporine are often ineffective because they block signals between T-
cells and transplants, but don't block the alarm that cells in shock send
to dendritic cells.
And what IS that alarm, exactly? That's the missing piece in
Matzinger's puzzle. It may be some kind of a chemical SOS, she says, but
there are other possibilities. "I'm in the same position as a
physicist who postulates a new particle and hopes she lives long enough
for someone to find it," says Matzinger. Given the excitement she has
already stirred up, a lot of people will probably help her look.
Neil Gross, Business Week, 2-6-95 )
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