the Body Attacks Itself
By Anne Underwood
Tuesday, December 2, 2003; 2:13 PM
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
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-Israel 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
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.
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