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 "nonself" has been the central metaphor of immunology since the early 1900s.

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 body's 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."

"PROVOCATIVE." To colleagues, Matzinger's theory itself 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 the NIH's Office of AIDS Research. It has already sparked heated discussion 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 at 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/nonself' 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, 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 immunosuppressing drugs such as cyclosporine are often ineffective because they block signals between T-cells and transplants but dmn'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.

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