* MS Article-Blocking Inflammatory Signals May Help In MS*

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Selectively Blocking Inflammatory Signals May Protect Mice From MS

A new way to preserve the cells that surround and protect nerves could

lead to new treatments for demyelinating diseases such a multiple

sclerosis, a research team reports in the May 2006, issue of the Journal

of Neuroscience.

The approach grew out of a novel explanation, quickly gaining followers,

for the mechanism of nerve damage caused by multiple sclerosis. Instead

of concentrating on the alterations that result in autoimmune assaults

on the nervous system, researchers led by Popko of the University

of Chicago have focused on a set of factors that prevent recovery from

the inflammatory attacks.

A series of papers from Popko's lab has demonstrated that

interferon-gamma -- a chemical signal used to activate the immune system

-- plays a critical role in damaging the cells that produce myelin, the

protective coating that lines healthy nerves. Interferon not only leaves

these cells, called oligodendrocytes, incapable of repairing the damage

but can also kill them directly.

" Interferon-gamma is not normally found in the nervous system, " said

Popko, the Jack Professor of Neurological Diseases at the

University of Chicago, " but it can gain entry after an inflammatory

flare-up. We previously showed how it harmed oligodendrocytes. Here we

confirm its direct harmful effects on those cells and demonstrate one

way of protecting them. "

The researchers produced a series of transgenic mice. In one set they

introduced genes that produced interferon-gamma within the central

nervous system. In another set they also introduced a gene (known as

suppressor of cytokine signaling 1, or SOCS1) that blocked the response

of myelin-producing cells to interferon-gamma.

Although transgenic mice with low levels of interferon-gamma showed no

symptoms of nervous system damage, 18 out of 20 mice exposed to higher

interferon levels developed difficulty walking, including mild to

moderate tremors, within two weeks of birth. Only four out of 20 mice

with both high interferon levels and the SOCS1 gene had symptoms.

On autopsy, mice with high interferon levels in the nervous system had

severe loss of oligodendrocytes, ranging from 20 to 40 percent. Those

with the protective SOCS1 gene lost only eight to 15 percent.

High interferon levels were also associated with loss of myelin sheaths

around nerve connections and unprotected axons in the brain. Again,

SOCS1 was able to reduce the damage.

" Together, " the researchers wrote, " these data demonstrate that

oligodendroglial expression of SOCS1 protects mice from the clinical and

morphological consequences of IFN-gamma expression in the central

nervous system during development. "

" We found this tremendously encouraging, " said Popko. " SOCS1 prevented

or reduced the harmful effects of interferon gamma on myelin-producing

cells. This study solidifies our suspicions about interferon's specific

role in demyelinating disease and suggests ways to block it. "

Although there is currently no reliable way to deliver SOCS1 directly to

the nerves of a patient with multiple sclerosis, this protective

approach could be combined with stem cell therapy to repair nerve

damage. Several research groups are already studying the use of stem

cells to repair damaged myelin sheaths, but in the long term those stem

cells would be vulnerable to ongoing immune-mediated damage.

But if stem cells could be engineered to resist harmful signals such as

interferon-gamma, they might be protected from the " harsh environment "

present in immune mediated demyelinated lesions, said Popko.

###

The National Institutes of Health and the Myelin Repair Foundation

supported the research. Additional authors include Roumen Balabanov and

Ji Yeon Lee of the University of Chicago, Krystal Strand of the

University of North Carolina, and April Kemper of Wake Forest University.