""Immunity"" Up-Ended?

Richard Schultz richard123 at delphi.com
Tue Apr 11 23:07:28 EST 1995

<plas_d at msdisk.wustl.edu> writes:
>Could you post a reference so that we can read up on this idea?
>Dave Plas
>Washington University
         (Dave Plas, M. Kuiper,  Xioling Chen, & others...Sorry, I've tried
several times to post this, so it may be a duplication)
	I saw 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 the theory in more detail,  using tissue
transplantation and tumors as examples.    I can imagine that finding the exact
nature of this "alarm signal"  that triggers the immune response could be the
foundation for  broad and really productive new medical research approaches and
R. Schultz
       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 early 1900's.
     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.                      	By Neil Gross, Business Week, 2-6-95

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