Irvine, Calif., October 1, 2001
UC Irvine researchers have discovered how to reverse the disabling nerve tissue damage affecting persons with multiple sclerosis, a finding that may produce treatments for those who have the debilitating disease.
In animal tests, UCI biologists Thomas Lane, Michael Liu and Hans Keirstead successfully stopped a process called demyelination, a disintegration of the fatty myelin tissue insulating nerve fibers that impairs the signaling function of the central nervous system. Through removing the factors causing the damage, the scientists found that the insulating tissue began to regenerate and normal nerve function began to return. Their findings are published in the October issue of the Journal of Immunology.
"We are excited by these findings because they show that the insulating tissue is capable of repairing itself if the causes of demyelination are removed," said Lane, an assistant professor of molecular biology and biochemistry. "While this doesn't represent a potential cure for multiple sclerosis, it does show that there are real possibilities to address the debilitating symptoms of this disease."
Demyelination is a central feature of multiple sclerosis, a chronic central nervous system disease that can cause blurred vision, poor coordination, slurred speech, numbness, acute fatigue and, in its most extreme form, blindness and paralysis. Some 350,000 Americans have this disease. Its causes are unknown, and symptoms are unpredictable and vary greatly in severity.
Lane and his colleagues targeted a set of molecules called chemokines, which work with immune response mechanisms in the body. When functioning properly, chemokines send signals to T lymphocyte cells (T-cells), which respond to repair injury and promote recovery from illness. However, in the instance of multiple sclerosis, an excessive amount of two specific chemokines, called CXCL-9 and CXCL-10, exist in the central nervous system and correlate with the inflammation of the myelin tissue covering nerve axons. In response to increasing amounts of CXCL-9 and CXCL-10, an overwhelming number of T-cells may respond and begin to destroy myelin tissue, which leads to a disruption of nerve signaling. In persons with multiple sclerosis, this process of demyelination can come in relapsing attacks or in a slow, degenerating process.
Lane and his colleagues used a mouse model of multiple sclerosis that is triggered by infecting the animals with a mouse hepatitis virus. After the mice began to show the effects of demyelination, including partial hind limb weakness and paralysis, they were injected with antibodies designed to block the activity of the CXCL-9 and CXCL-10 molecules in the central nervous system.
While treatment with antibodies specific for CXCL-9 showed no effects, application of antibodies specific for CXCL-10 blocked signaling to the T-cells. The researchers then began to notice a reversal in demyelination followed by a regeneration of the myelin tissue. Soon after that observation, crippled mice began to resume normal hind limb function. However, when Lane and his colleagues ceased to apply the CXCL-10 antibodies to these mice, demyelination resumed and limb weakness and paralysis returned.
"Because of these results, we believe that there is strong evidence that the CXCL-10 molecule is the key in starting the process of demyelination," Lane said. "The results also document the feasibility of treating demyelinating diseases with antibodies, which will be our next research direction."
Lane and his colleagues are following these findings by exploring the molecular mechanisms of myelin repair. A patent is pending on the research method. The National Institutes of Health, the National Multiple Sclerosis Society and the Reeve-Irvine Research Center at UCI supported the research.