By David N. Leff

Police officials and Hollywood producers are all too familiar with recidivism: A convicted wrongdoer completes his sentence, goes straight for a while, then relapses into a life of crime

In multiple sclerosis, this off-again-on-again perpetrator is myelin, a rubbery molecule pervading the brain¿s white matter. It wraps a protective sheath around axons in the mammalian nervous system. Myelin is directly responsible for the slow, insidious worsening and erratic waning of MS. This incurable autoimmune disease afflicts more than 1 million people worldwide with progressive symptoms of visual loss, double vision, speech impairment, weakness, numbness, mood alterations, poor coordination and movement.

These and other MS signs tend to flare up and die down in unpredictable relapses and remissions ¿ pathological recidivism. They correlate with the two phases of myelin wrapped around axons ¿ demyelination (frittering of the insulating sheath) and remyelination (self-triggered restoration of the circum-axonal myelin layer). Without myelin, axons can¿t fire.

¿What triggers these two phases of myelin?¿ asks molecular biologist/immunologist Jenny Ting, at the University of North Carolina, Chapel Hill. ¿That¿s what we¿re all trying to find out. In particular, what causes remyelination? There are lots of reasons, like [asking]: Why do you have cancer?¿¿

Ting is senior author of an article in the November 2001 issue of nature neuroscience titled: ¿TNFa promotes proliferation of oligodendrocyte progenitors and remyelination.¿ The article¿s first author is graduate student Heather Arnett.

¿Remyelination has been very difficult to study in a living organism,¿ Ting told BioWorld Today. ¿That¿s the phase that we really want to accelerate. So what we¿ve done is use knockout mice that lack cytokine genes and their receptors to see if their demyelination got worse or better.

¿Some of the molecules we focused on,¿ Ting continued, ¿are typically thought of as just not good for the brain. TNF ¿ tumor necrosis factor ¿ is one of these. Most people in the field have thought that TNF makes MS worse, not better, and should be suppressed. In recent clinical trials, investigators tried to block TNF function, and their results proved disappointing ¿ sometimes even worse than in the untreated group. We asked why.¿

Caution: Two Receptors, One Benefit

¿What we found in our [knockout] mice is that one has to be very careful about when and how to block TNF, since that immune-system cytokine can bind to more than one receptor,¿ Ting said. ¿The one we discovered to be most important for remyelination is TNF receptor 2. TNF-1 has very low effects. What we did in our model in vivo system was to study knockout mice lacking TNFR1 and TNFR2 to follow the course of demyelination ¿ destruction of the brain¿s white matter ¿ and remyelination, its restoration.

¿During the remyelination phase,¿ she said, ¿we found that mice lacking TNF-alpha or TNFR2 receptors do not remyelinate as quickly ¿ in fact they¿re greatly delayed. The beauty of our system is that after demyelination, we can also see a very predictable onset of remyelination, which is where the repair happens. My graduate student, Heather Arnett, did this experiment very simply with a toxic chemical called cuprizone, [which] is a copper-chelating agent, which removes copper from the body, and has no clinical use, because it causes demyelination as a side effect. Arnett applied a method using a very low dose of cuprizone, such that we didn¿t see any peripheral reactions ¿ no adverse effects on liver, blood and so forth ¿ but its effect seemed to be more concentrated in the brain. The whole field does not understand why cuprizone would cause brain problems. It¿s very localized, very predictable. So we didn¿t have to guess when our myelin-negative mice were going to come down with a pathological problem.

¿First Arnett fed mice low levels of cuprizone ¿ sufficient to cause brain damage,¿ Ting said, ¿but without lesioning other parts of the body by demyelination. Then she removed the chemical, and the normal mice slowly recovered by way of remyelination. [Knockouts] lacking TNF-alpha did not. That¿s how we followed these two phases of MS-mimicking disease.

¿What we reported in our paper,¿ she said, ¿is that TNF is not so beneficial during the demyelination phase, but very good in the remyelination phase. Demyelination is the primary problem. So that¿s where you have MS, the cause of which we don¿t really know. Some people believe it¿s because of immune-system autoimmunity. Others think it may have an epidemiology component.¿ She explained: ¿If you have mouse models of MS, there are certain viruses that can mimic the disease. People who live in northern latitudes are more prone to catching it. So I think MS poses a very broad-based problem, all leading to demyelination.¿

Second Cytokine Joins TNF Hit Parade

While Ting and her team were confirming TNFR2¿s pro-remyelination, anti-recidivistic properties, a second immune-system cytokine molecule surfaced: ¿Another paper, published last month in the Journal of Neuroscience,¿ she said, ¿shows that interleukin-1 does the same thing as TNFR2; it¿s also required for remyelination. So here we have two molecules that typically we always think about as, You should suppress, suppress, suppress.¿ What we found was that this is not the case; that IL-1 and TNF are made for a reason ¿ probably to accelerate the process of myelin repair. Both of these molecules have lots of effects ¿ some good, some bad. Although they can often cause cell damage, they can certainly protect cells. They have lots of ways to turn proteins on. So they have large numbers of consequences.¿

The other starring player in the myelin drama is that white matter¿s parental cell, the oligodendrocyte progenitor, which makes myelin.

¿Right now,¿ Ting said, ¿we¿re trying to see how these molecules can change, in vivo and in cell culture.¿ There are definitely fewer oligodendrocytes in MS. That and demyelination are the disease¿s main problems. But I think we¿ll still be far from using this information ¿ when we get it ¿ for any clinical application. If one could figure out why TNFR2, but not TNFR1, is required for mice, and does the same thing happen in humans, that would be critical, and very nice ¿ and we¿re pretty far from it.¿