Relapses Prevented In Mouse Model Of Multiple Sclerosis: Research Aimed At Treating Relapses In Human MS

October 28, 1998

Researchers at the University of Pennsylvania Medical Center have discovered that antibodies to a common inflammatory-response protein can prevent relapses in an animal model of human multiple sclerosis. "We have been able to prevent relapses in the mouse version of multiple sclerosis using anti-interleukin-12 antibodies for the first time," says Mohamad Rostami, MD, PhD, professor of neurology at Penn's School of Medicine. "Most treatments for MS are first tried out in the experimental allergic encephalomyelitis, or EAE, animal model of MS, before being tested in humans, so this research represents another possible therapy for MS patients." Rostami, Cris Constantinescu, a doctoral student in Rostami's laboratory, and colleagues report their findings in the November 1 issue of the Journal of Immunology.

MS, a neurological disorder, affects 300,000 or more young adults in the United States. Many with the disease suffer from relapses after the initial onset of such symptoms as numbness and paralysis. Trying to remedy these relapses is the research focus of Rostami and his collaborators.

Although the origins of MS remain mysterious, the disorder is considered an autoimmune disease. Immune system cells called T cells cause inflammation in the brain and spinal cord, which is eventually followed by demyelination, the breakdown of the protective sheath that surrounds nerve axons. Certain T cells work in conjunction with proteins called cytokines to cause the damage. "In brains of EAE mice, we saw that the cytokine interleukin-12 is upregulated when there's a relapse and downregulated during a remission," says Rostami. "We believe that both MS and EAE are induced by the Th1 type of T cell. Th2 cells, another type of T cell, are important for recovery from inflammation."

As part of MS-induced inflammation Th2s will try to fight the damage that Th1 cells cause. Rostami reasoned that if the cytokine balance could be changed to decrease the number of Th1 cells -- and allow Th2 cells to do their job -- demyelination could be suppressed. To do that, the researchers neutralized interleukin-12 with an antibody, which in turn suppressed the production of Th1 cells. Therefore, with less Th1 cells, the remaining Th2 cells were free to fight the inflammation caused by the Th1 cells.

In past experiments, researchers gave treatments to animals before disease symptoms were first seen, then waited to see if the EAE disorder would progress. Instead, Rostami's team waited until the mice had their first relapse before administering the experimental treatment. This design more accurately reflects the situation in humans, in which patients are given a treatment after the onset of a relapse.

"Those mice that received the antibody to interleukin-12 didn't relapse," notes Rostami. The same results hold true for superantigen-induced relapses, a model that is similar to human MS relapses triggered by viral or bacterial infections.

Drugs used to treat MS relapses such as interferons and Copaxone only decrease the number of relapses by one-third, notes Rostami, "so, we are always looking for better therapies." The next step is to produce the human form of the anti-interleukin-12 antibody and administer it to MS patients at the start of a relapse.
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This research was supported by the National Institutes of Health.

Editor's Note: Dr. Rostami can be reached directly at 215-662-6557 or rostamia@mail.med.upenn.edu

The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website (http://www.med.upenn.edu); EurekAlert! (http://www.eurekalert.org), a resource sponsored by the American Association for the Advancement of Science; and Newswise (http://www.newswise.com).
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University of Pennsylvania School of Medicine

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