When The Body Attacks Itself

by Anne Underwood | Dec 08 '03 Newsweek

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 seriously 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, director of the Immune Tolerance Network at 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 London posed that very question in the mid-1980s. Doctors scoffed. But three drugs for rheumatoid arthritis emerged from their research, and the same drugs are also proving useful for conditions like Crohn's disease and juvenile arthritis. This year Maini and Feldmann won the Lasker Award for clinical medical research. And some of their colleagues are talking Nobel Prize.

Drug companies are eager to expand this approach into therapies for other autoimmune diseases, which have been on the increase since the 1950s, but have few good treatments available today. Translating principle into practice will not be easy, however. 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 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. In a small clinical trial, they tested an anti-TNF antibody in 20 patients who had failed to respond to other treatments. Within hours, the recipients started feeling better. In six weeks, they were climbing stairs and even golfing. Today there are three TNF blockers on the market for rheumatoid arthritis-Remicade (which Maini and Feldmann used), Enbrel and Humira.

But not all patients with rheumatoid arthritis respond to these costly TNF blockers-nor does anti-TNF therapy hold the master key to all autoimmune diseases. "There may be some therapies that are broadly applicable across a wide range of disorders, and others that are particular to one disease," says Bluestone. So doctors are targeting other immune-system components, like B cells and T cells, in an attempt to tame various autoimmune problems. Genentech's drug Rituxan, a bioengineered antibody against B cells, is now in early trials for lupus, the most challenging of all autoimmune diseases because it affects not just one type of tissue, but organs throughout the body.

Muzzling the immune system's pit bulls is only one approach to treating immune disorders. 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-lsrael Institute of Technology in Haifa published a paper showing that the immune system makes its own anti-TNF antibodies-but only when it's also producing a lot of TNF. Karin detected antibodies in patients with rheumatoid arthritis, but not osteoarthritis (a degenerative disease), nor in normal, healthy people. "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 learn to retrain the immune system so that it no longer needs drugs to make it behave. 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. The antibody latches onto the T cells that destroy insulin-producing beta cells in the pancreas. In the process, it blocks one of the crucial receptors on the T cells that is needed to activate an attack.

Together with Dr. Kevan Herold of Columbia University, Bluestone has tested the antibody 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. Bluestone notes that the effect is starting to wear off, and the participants may need booster shots. But, he adds, "what's really exciting is that the T cells seem to remain in the pancreas and retrain other T cells."

Unfortunately, even if it works perfectly, the antibody is 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 irreversible damage has been done. Beginning next year, the Dinora Trial will test Remicade in patients who have had symptoms of rheumatoid arthritis for no longer than 12 weeks. The goal is long-term remission. Other doctors are trying to uncover ways of testing for autoimmune diseases before symptoms even emerge. They have their work cut out for them.

Newsweek U.S. Edition