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 Brian 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 Miller 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.
John Easton | EurekAlert!
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