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Molecule linked to autoimmune disease relapses identified at Stanford

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    Molecule linked to autoimmune disease relapses identified at Stanford Contact: Mitzi Baker mabaker@stanford.edu 650-725-2105 Stanford University Medical Center
    Message 1 of 1 , Dec 3, 2006
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      Molecule linked to autoimmune disease relapses identified at Stanford

      Contact: Mitzi Baker
      Stanford University Medical Center

      Public release date: 3-Dec-2006

      Contact: Mitzi Baker
      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 (650) 723-7897

      This study was supported by the National Institutes of Health, the
      National Multiple Sclerosis Society, the Phil N. Allen 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. Edward Haws, an undergraduate at
      Brigham Young University; Susan Zhang, a Stanford undergraduate, and
      Raymond 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
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