'Danger model' challenges old assumptions

March 1, 2005

According to Polly Matzinger, Ph.D., the immune system operates in a sleeping mode until injured tissues or cells waken it with alarm signals.

According to Polly Matzinger, Ph.D., the immune system operates in a sleeping mode until injured tissues or cells waken it with alarm signals.

Dr. Matzinger, who heads the T-cell Tolerance and Memory section at the National Institutes of Health's (NIH) Laboratory of Cellular and Molecular Immunology in Bethesda, Md., explains that all tissues have sentinel or dendritic cells. In the epidermis, these are the Langerhans cells. Other cells talk to the Langerhans, saying either "I'm okay" or "I'm not okay."

Triggers When triggered by an injured skin cell, the Langerhans "drink up" their environment - debris from dead cells, viruses - and deliver it to a local lymph node, where they display this information to passing white blood cells. These, in turn, get to work, repairing any damage reported.

The basic idea of the old model, she says, is that each person's immune system learns what is "self" in utero. Anything that arrives later is "not self." The body fights "not self" and leaves the rest alone - except when it's in a disease state.

Dr. Matzinger contends that the old model has some large holes. It doesn't explain why mothers fail to reject fetuses, why some transplants are rejected, why people get autoimmune diseases, why filaria and malaria don't cause immune responses, why the body doesn't reject tumors and the continued presence of pathogens.

And to further her point, she asks, "What has immunology contributed to medicine?"

According to Dr. Matzinger, not much.

"Maybe monoclonal antibodies for diagnostics, but that's about it. Vaccines were developed long before the field of immunology was born. And immunologists still don't have an explanation for autoimmune diseases or cancer."

Danger model, practically speaking Mothers don't reject fetuses or tumors because the body does not react against healthy, growing tissue. Some pathogens have evolved in ways that minimize damage and circumvent the immune system.

"People think the body rejects transplants because they are foreign. That may be partly true, but it's also because surgeons do a lot of damage. If they did less, they might be able to get transplants to take without using immunosuppressant drugs," Dr. Matzinger says.

To bolster this argument, she points out that unmatched tissues from living kidney donors have a lower rejection rate than matched cadaver kidneys, which have been subjected to more trauma.

"Cells coming up from the dermis to the epidermis die as the skin grows out," she tells Dermatology Times. That's programmed normal cell death. But if a cell dies badly, it provokes an immune response. There's some evidence, developed by Anthony Rosen, M.D. at Johns Hopkins, that scleroderma is caused by an immune response to bad cell death."

Finally, Dr. Matzinger argues that vaccines for tumors aren't working because they are based on the wrong model. With measles, a vaccination followed by a booster activates the immune system and creates an army of white blood cells that wait for the virus. Upon returning, the virus causes new damage, rekindling an immune response.

With tumors the process is different. Initially, the immune system remains dormant because it recognizes them as healthy cells. If triggered into action by a vaccine, the immune system has to perform flawlessly, killing 100 percent of tumor cells; otherwise, the mass will continue to grow.

Preliminary results from Dr. Matzinger's melanoma research with mice indicate that remission rates improve with the number of booster shots.

She says, "For a vaccine to work, you have to keep boosting until the tumor is gone."

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