*MS Article* Molecule Key In MS?

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Molecule linked to autoimmune disease relapses identified at Stanford

Contact: Mitzi Baker

mabaker@...

Stanford University Medical Center

Public release date: 3-Dec-2006

Contact: Mitzi Baker

mabaker@...

Stanford University Medical Center

STANFORD, Calif. -- The ebb and flow of such autoimmune diseases as

multiple sclerosis, lupus and rheumatoid arthritis has long been a

perplexing mystery. But new findings from the Stanford University School

of Medicine bring scientists closer to solving the puzzle, identifying a

molecule that appears to play a central role in relapses.

The study, to be published in the Dec. 3 advance online edition of

Nature Immunology, lays the groundwork for a way to determine when a

relapse is about to occur, and could eventually lead to a treatment to

prevent relapses. " Right now, there is no good blood test to evaluate

when a person is going to have a flare-up, " said senior author Larry

Steinman, MD, professor of neurology and neurological sciences. " If we

had one, we might be able to give them prophylactic preventive

medication. "

The current study had its genesis five years ago: In a paper published

in 2001 in the journal Science, Steinman found that a protein called

osteopontin was abundant in multiple sclerosis-affected brain tissue,

but not in normal tissue. Since then, other groups have confirmed that

osteopontin is elevated just prior to and during a relapse of the

disease in M.S. patients.

Although the protein had been known to play a role in bone growth, it

was unclear why it would be associated with multiple sclerosis, which

results when the immune system attacks the protective myelin sheath

surrounding nerve cells.

To explore this question, Eun Mi Hur, PhD, who was then a graduate

student in Steinman's lab, began using a mouse model of multiple

sclerosis (experimental autoimmune encephalomyletis, or EAE) to

investigate how osteopontin could cause these flare-ups. She and

Steinman gave osteopontin to mice that had already experienced

paralysis, similar to that of an M.S. patient, and found that the mice

then experienced a relapse of the disease.

The researchers also found that the relapse would occur sometimes in an

area of the brain other than the site of the original attack. For

example, after receiving the osteopontin, some animals that had

previously suffered paralysis became blind from a condition called optic

neuritis. One feature of multiple sclerosis is that the flare-ups can

affect different parts of the nervous system at different times.

" When I saw that all mice with EAE relapsed and died from the disease

after about a month of osteopontin administration, I was surprised, "

said Hur, the study's first author who is now a postdoctoral scholar at

Caltech. " I got a strong belief that a high level of osteopontin in

patients' blood and tissue is a major contributor of the relapse and

progression of the disease. "

Through the mouse studies and molecular characterizations, Hur and

Steinman showed that osteopontin - produced by immune cells and brain

cells themselves - promotes the survival of the T cells that carry out

the damaging attack on myelin; by increasing the number of these T

cells, osteopontin increases their destructive potential. These results

could be applicable to many other autoimmune diseases, including

rheumatoid arthritis, type-1 diabetes and lupus.

Indeed, the effect of osteopontin may severely alter the way the immune

system works. Normally, after the immune system does its job -

eradicating a microbe, for instance - the response is then dialed down.

If this didn't happen, the immune response would go on indefinitely.

Imagine a cold or an attack of poison oak that would last forever.

One of the ways that the immune response is muffled is that the

activated T cells die in a process known as apoptosis. That is precisely

what osteopontin seems to prevent. Osteopontin lets the T cells linger

in the blood, ready to attack again. " We don't know exactly what

triggers that new attack but the cells certainly are around and ready to

do it, " said Steinman. So scientists now face the challenge of figuring

out how and why osteopontin is produced. " We're back to the

chicken-and-the-egg problem, " said Steinman. " We know the egg, so why

did the chicken lay it " That is a trickier problem to work out. "

Even without knowing the answer to that question, there is one inviting

practical use of their observations: Osteopontin could be used as a

marker of an impending relapse. What's more, if the protein could be

blocked, it might thwart the relapse from ever occurring. Steinman's lab

is working to develop antibodies to inactivate the protein's effect.

" It's still a long road between saying we want to do it and getting the

antibodies, getting it approved by the FDA and getting it tested, " said

Steinman, " but we are determined to do that. "

Still, Steinman offered a caveat. Researchers may find that blocking

osteopontin has undesirable side effects. The protein may serve other

purposes in addition to promoting survival of immune cells. It could

also be vital to the body's ability to produce myelin, a function that

could cause severe problems if disrupted. " Like a lot of important

biological molecules, osteopontin has a Janus-like quality - a bad side

and a good side, " Steinman said. " We're going to be extremely lucky if

we give the antibody opposing osteopontin and derive just the good side:

We stop the autoimmune attack but don't interfere with the survival of

other cells. "

Further study will determine whether thwarting osteopontin's effect

yields new types of treatments for autoimmune diseases, but regardless,

it is likely to lead to discoveries in a host of areas. " I think

osteopontin will turn out to be important in a lot of processes,

spanning autoimmunity to stem cells, " said Steinman. " It's probably

going to turn out to be a very basic growth factor. "

###

EMBARGOED FOR RELEASE UNTIL: Sunday, Dec. 3, 2006, at 11 a.m. to

coincide with advance online publication in Nature Immunology BROADCAST

MEDIA CONTACT: Margarita Gallardo at

(mjgallardo@...)

This study was supported by the National Institutes of Health, the

National Multiple Sclerosis Society, the Phil N. Trust, a Stanford

Graduate Fellowship, a Korean Government Overseas Scholarship and a

National Multiple Sclerosis Society Career Transitional Award. Other

authors of the study are: Sawsan Youssef, PhD, a postdoctoral scholar in

neurology and neurological sciences; M. Haws, an undergraduate at

Brigham Young University; Zhang, a Stanford undergraduate, and

Sobel, MD, professor of pathology.

Stanford University Medical Center integrates research, medical

education and patient care at its three institutions - Stanford

University School of Medicine, Stanford Hospital & Clinics and Lucile

Packard Children's Hospital at Stanford. For more information, please

visit the Web site of the medical center's Office of Communication &

Public Affairs at http://mednews.stanford.edu.

http://www.eurekalert.org/pub_releases/2006-12/sumc-mlt120106.php