New Immune Theory

[Richard Schultz]

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 & 
effective treatments.


"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 
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 )