When The Body Attacks Itself

The immune system is a thing of beauty--subtle enough to distinguish dangerous invaders like viruses from benign interlopers such as food; clever enough to recognize when the body's supposedly friendly cells turn cancerous and should be eliminated. But the immune system can also go awry. When it begins mauling healthy tissues, the result can be any one of 80 autoimmune diseases such as lupus or rheumatoid arthritis. "It's the price we pay for having such a dynamic, finely balanced system," says immunobiologist Jeffrey Bluestone of the University of California, San Francisco.

Must we limit ourselves to treating the symptoms of these disorders, or could we modulate the immune system itself? Immunologist Marc Feldmann and rheumatologist Ravinder Maini of Imperial College in London posed that very question in the mid-1980s. Doctors scoffed. But three drugs for rheumatoid arthritis emerged from their research. And this year Maini and Feldmann won the Lasker Award for clinical medical research.

Drug companies are eager to expand this approach into therapies for other autoimmune diseases, which have been on the increase since the 1950s, but it won't be easy. The immune system is a vast network with a bewildering array of warriors--from antibody-making B cells to various kinds of T cells that can enhance antibody production, kill virus-infected cells, initiate inflammation and finally shut down an immune attack. B cells and T cells also make more than 100 types of helpers called cytokines that assist in orchestrating every aspect of the immune assault.

Maini and Feldmann in the 1980s zeroed in on one such cytokine called tumor necrosis factor (TNF). It derives its name from its ability to kill cancer cells, but in excess it also initiates the inflammation of rheumatoid arthritis. Today anti-TNF therapy is proving useful for a range of inflammatory conditions. But it does not hold the master key to all autoimmune diseases, so doctors are targeting other immune-system components in a search for new treatments. Genentech's drug Rituxan, a bioengineered antibody against B cells, is now in early trials for lupus, the most challenging autoimmune disease because it affects organs throughout the body.

Muzzling the immune system's pit bulls is only one approach. Another--in theory at least--is to boost the components of the immune system that naturally rein in attacks. Last month immunologist Nathan Karin at the Technion-Israel Institute of Technology in Haifa published a paper showing that the immune system can make its own anti-TNF antibodies when it needs to. "If we could harness these antibodies," he says, "we might be able to teach the body to amplify its own beneficial response."

In the long run, however, the goal of doctors (if not drug companies) is to retrain the immune system so that drugs are no longer needed. Sound impossible? "I've staked my whole career on it," says Bluestone. Several years ago he developed a bioengineered antibody to treat type 1 diabetes; he has tested it in 23 newly diagnosed patients. Two years later, those who received just two weeks of treatment at the outset are making twice as much insulin as patients who didn't receive the antibodies. "What's really exciting is that the T cells seem to remain in the pancreas and retrain other T cells," he says.

Unfortunately, even if the treatment works perfectly, it's not a cure. By the time type 1 diabetes is diagnosed, the pancreas has lost 80 to 90 percent of its insulin-making ability. That's why the ideal time to treat autoimmune diseases is early on, before symptoms even emerge. Doctors have their work cut out for them.