Reprogramming the immune system

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Reprogramming the immune system

Approach uses the body's own cells to fight multiple sclerosis

In multiple sclerosis, immune-system cells called T cells attack and damage

the myelin sheath that protects nerve cells, or neurons.

By Charlene Laino

MSNBC

Jan. 23 - It's like pouring gasoline on a fire to put it out. Yes, you read

correctly: that's the best way to describe a novel approach that shows

promise for treating multiple sclerosis using an extremely large dose of the

very substance that is causing the disease to begin with.

FOR THE first time, scientists have shown that the experimental

approach works in non-human primates with multiple sclerosis. And there's

every reason to believe, they say, that the same tactic could help stomp out

symptoms in humans suffering not only from MS, but also from other

autoimmune diseases, such as rheumatoid arthritis and diabetes.

The feat is the latest to grow out of a new molecular-level

understanding of autoimmune diseases, the umbrella term for some 40-plus

conditions in which the body's immune system - its first line of defense

against foreign invaders - runs amok.

Researchers have known for years that autoimmune diseases result when

a malfunctioning immune system mistakenly recognizes certain cells in the

body as the enemy and launches an all-out attack. In multiple sclerosis, the

myelin sheath - the protective covering that surrounds nerve cells in the

brain and spinal cord - is the target.

More recently, experiment showed that specialized immune-system cells

called T-helper cells are the key players, the culprits that produce

substances that attack and damage the myelin sheath. The result is

devastating for the millions of Americans with the disease: fatigue, dim or

blurred vision, disturbed speech, memory loss, muscle weakness, even

paralysis. The " lucky " ones merely suffer mild weakness for decades (though

always wondering if their condition will worsen); others steadily

deteriorate from repeated attacks.

Meanwhile, scientists were gaining a better understanding of a

well-honed immune system - a system in which the same T cells that wreak

havoc in MS are gallant warriors. It became clear that like soldiers,

T-helper cells sit ready for invasion from a foreign invader, be it a flu

bug, food-borne bacteria or other pathogen. Then, as soon as they recognize

the enemy, these T cells turn into commanding officers of sorts and begin

multiplying until an entire army is set to fight.

" But like any potent weapon, you want to control how much is

deployed, " says the National Institutes of Health's Dr. Lenardo. " If

the cells just kept multiplying ... you'd have a surfeit of T cells, very

potent activators that can actually kill you - as happens in toxic shock

syndrome. "

PROGRAMMED FOR DESTRUCTION

Fortunately, every cell has a built-in suicide mechanism. " When there

are too many soldiers, they are programmed to self-destruct, " he says. " A

healthy immune system doesn't let your T cells grow uncontrolled and kill

you. "

Several years ago, Lenardo, a researcher at the National Institute of

Allergy and Infectious Diseases' laboratory of immunology, decided to put

the new knowledge about the immune system in general and MS in particular to

a test. Since MS is an autoimmune disease in which T-helper cells are

activated that shouldn't be, Lenardo reasoned that he could thwart the

disease if he could just activate T-helper cells' built-in suicide

mechanism.

Working at first in the lab, Lenardo proved his point. As expected,

T-helper cells exposed to small amounts of the proteins making up the myelin

sheaths were stimulated to attack the sheaths.

But, paradoxically, when these activated T-helper cells were exposed

to large amounts of the same proteins, they died off. " Instead of robust

proliferation, which is what we expected, we got self-destruction, " says

Lenardo. " We observed negative feedback. "

Next, Lenardo tried the experiments in mice, " with very dramatic

results. Not only did the MS mice become healthy, but the disease-causing T

cells were actually eliminated, " he says.

MONKEY BUSINESS

In the latest test, nine male marmoset monkeys were injected with

just enough myelin proteins to stimulate their T cells to attack myelin

sheaths, inducing a disease very similar to MS in humans. Three monkeys then

received additional large doses of myelin proteins, three got moderate

doses, and three received nothing.

About three months later, all three of the untreated monkeys showed

symptoms of the disease. In contrast, none of the primates who got large

doses of myelin had symptoms. The moderate-dose group didn't fare as well,

with two showing symptoms, though less severe ones than their untreated

counterparts. The report appears in the February issue of the Journal of

Immunology.

Imaging scans of the animals' brains further validated the

observations. Magnetic resonance images revealed severe damage to the myelin

sheaths in two of the untreated monkeys and one of the moderate-dose

monkeys. Minor damage did occur in the large-dose group, indicating the

disease process had not been completely thwarted although it had been

greatly suppressed, Lenardo says.

" They've re-educated an immune system gone awry, " says Dr. O

'Looney, director of biomedical research at the National Multiple Sclerosis

Society in New York. " This certainly holds great promise. "

One of the most exciting aspects of the new work is that it marshals

the body's own, nontoxic resources to fight off the disease. Similar to

chemotherapy for cancer, current treatments for MS and other autoimmune

diseases are atom bombs of sorts, killing or suppressing everything in their

wake, good or bad.

" Conceptually, we have a very powerful new tool, " Lenardo says. " It

selectively homes in only on those cells causing the disease rather than

shutting down the entire immune system. "

There are even advantages over other immune-based approaches to

autoimmune diseases, he says. " The others just paralyze T cells, but they

could wake back up. This actually gets rid of them. "

With human testing still on the horizon, it's too early to say

whether Lenardo's approach is best. But with one in 20 Americans victim of

one autoimmune disease or another, at enormous personal cost in pain and

suffering and at monetary costs topping $100 billion each year, it's

certainly worth a shot.