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MS study may have treatment implications


Two Kinds of Multiple Sclerosis

Two Kinds of Multiple Sclerosis
By tscott

Source: Stanford School of Medicine (http://med.stanford.edu)

By Bruce Goldman, Science Writer, Office of Communication & Public AffairsStanford University School of Medicine

There may be two distinct versions of multiple sclerosis, a study in both animal models and human blood samples suggests. Whats more, a patients responsiveness to the most popular first-line drug for this episodic and all-too-often recurring autoimmune condition seems to depend on which version that patient has.

If these findings are confirmed in larger human studies and by other laboratories, people with multiple sclerosis might someday be able to take a simple blood test to see whether they are likely to respond to treatment with the standard multiple-sclerosis therapy, said senior study author Lawrence Steinman, MD, the George A. Zimmerman Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine.

Public health may benefit, too, Steinman said, as the cost savings from being able to predict in advance which patients will benefit from beta-interferon, a costly bioengineered drug whose global sales come to some $4 billion a year, could be considerable.

Beta-interferons overall efficacy is only fair, he said, with perhaps half of all multiple-sclerosis patients experiencing an average one-third reduction in recurrences. Plus, its discomfiting side effects flulike symptoms can make compliance an issue for patients, especially given the drugs iffy efficacy.

Many nerve cells in mammalian brains and peripheral tissues must convey electrochemical impulses over great distances, and quickly. Long, wirelike projections that transmit these cells signals to other nerve or muscle cells are coated by myelin, a natural substance whose insulating properties sustain the impulses strength and increase their speed.

Multiple sclerosis is triggered when, for reasons that are not yet clear, immune cells called T cells attack the myelin sheathing, causing symptoms including paralysis and blindness. The condition affects 400,000 people in the United States, according to the National Multiple Sclerosis Society.

A few years ago while still a PhD student at the University of Alabama, the studys first author, Robert Axtell, had shown that, as in people with multiple sclerosis, beta-interferon can reverse paralysis in mice with EAE. But it turns out that EAE can be induced by two different autoimmune pathways, characterized by different patterns of secretion by T cells.

Like nerve cells, immune cells also communicate with one another across long distances, but they accomplish this through various chemicals called cytokines that they secrete into the blood. Immune cells on the receiving end of a cytokine signal may respond quite differently, depending on the particular type of cytokine to which they are exposed. Two cytokines called gamma-interferon and IL-17, for example, tend to induce the kinds of inflammatory immune-system arousal that can trigger multiple sclerosis.

Axtell (now a postdoctoral scholar in Steinmans lab), Steinman and their colleagues were able to induce two superficially similar forms of EAE in mice by directing the myelin-attacking T cells to predominantly secrete either gamma-interferon or IL-17, respectively. The researchers found that beta-interferon improved the condition of animals whose EAE had been induced by gamma-interferon-secreting T cells, but exacerbated symptoms in those whose EAE had been induced by IL-17-secreting T cells.

Intrigued, the investigators turned to humans. Another postdoctoral scholar in the Steinman lab, Brigit deJong, MD, the studys second author, had previously been involved in research in Amsterdam in which multiple-sclerosis patients were treated with beta-interferon and meticulously followed up. The Stanford group obtained blood samples taken from 26 of these patients both before and about two years after the initiation of treatment. Without knowing which samples came from patients who had responded well or poorly to beta-interferon treatment, they went about measuring IL-17 levels in those samples.

Eventually, patients follow-up histories were revealed to the researchers and their measured IL-17 levels were paired with their post-treatment progress. A clear pattern emerged. Measurements of a particular variety of IL-17, called IL-17F, clustered at either very high or very low levels in individual patients blood. Those with very low detectable blood levels of IL-17F responded well to beta-interferon treatment, experiencing no relapses or instances of required steroids (to quickly shut down a malfunctioning immune system). But patients with very high IL-17F levels about one out of three subjects responded poorly by the same criteria. In fact, said Steinman, there is some evidence that beta-interferon actually worsened these patients conditions.

Steinman cautioned that the results need to be confirmed in larger patient groups, in his lab as well as in others. But, he said, I think this has the potential to transform the way we take care of people with multiple sclerosis. He said a simple, already available blood test could spare many patients the inconvenience and side effects and spare the health-care system the expense of a drug that most likely wont do any good. The other side of the coin is that beta-interferon, if its given only to those who are predisposed to respond to it, could turn out to be a far better drug than we ever imagined.

Although Steinman and his colleagues do not stand to benefit in any direct way from this work, Stanford Universitys Office of Technology Licensing has filed a patent application on the use of the blood test. Earlier work by Steinman, proceeding from animal models to clinical trials, led to the development of another blockbuster multiple-sclerosis drug, natalizumab, marketed under the trade name Tysabri.

Several other scientists from Stanford and elsewhere co-authored the Nature Medicine study, which was funded by the National Multiple Sclerosis Society. Axtells former PhD advisor, Chander Raman, PhD, of the University of Alabama-Birminghams Department of Medicine shares senior authorship with Steinman. More information about Stanfords Department of Neurology and Neurological Sciences, which supported the work, is available at http://neurology.stanford.edu/.

Note: This article was shared with permission from Stanford School of Medicine and was originally published at http://med.stanford.edu/ism/2010/march/sclerosis.html. Copyright Stanford University School of Medicine Office of Communication & Public Affairs.

This entry was posted on Tuesday, April 6th, 2010 at 6:50 am and is filed under News Alerts, Studies. You can follow any responses to this entry through the RSS 2.0 feed.


MS study may have treatment implications

Researchers find a connection between a particular protein that regulates immune function and patient response to medication


From Monday's Globe and Mail Published on Monday, Mar. 29, 2010 8:55AM EDT Last updated on Monday, Mar. 29, 2010 9:00AM EDT

Multiple sclerosis researchers have found a connection between a particular protein that regulates immune function and patient response to medication, a link they hope may be used to help predict who will benefit from a popular treatment.

The finding, included in a study published online yesterday in the journal Nature Medicine, raises the possibility there are two distinct kinds of multiple sclerosis that dictate whether an individual will benefit from taking interferon-beta, one of the most commonly prescribed drugs to treat the disorder.

It's a pretty big aha' moment I think in the field of multiple sclerosis, said Lawrence Steinman, professor of neurology at Stanford University and lead author of the study.

The new research comes at a time when much of the public discussion of multiple sclerosis is fixated on a new theory and experimental procedure from Italian medicine professor Paolo Zamboni. He believes MS is a vascular condition, caused by blocked or malformed veins responsible for draining blood from the brain, and can be treated with surgery.

Although a significant amount of money is being earmarked to study the theory's validity, more conventional research into the cause of MS and potential treatments continues. Doctors have long known that some patients don't respond well to interferon-beta, a front-line MS drug, but the reason has never been clear.

Dr. Steinman and his colleagues, including Canadian post-doctoral fellow Robert Axtell, think they may have found the answer. They discovered that a group of MS patients who didnt respond to the medication all had high levels of Interleukin-17 (IL-17), a cytokine or protein that helps regulate the immune system.

Its an important connection because it opens the door to the possibility MS patients may one day be able to have a simple blood test to determine if interferon-beta will work for them, according to the study.

That would help patients make a rational decision about their course of treatment and be more aware of the potential outcome, Dr. Steinman said.

But it could also represent a significant savings in medication costs. Identifying which patients wont benefit from interferon-beta could help unnecessary prescriptions and the price tag that goes along with them, Dr. Steinman said.

That [blood] test would have a great impact, he said.

Their research was funded by grants from the U.S. National Institutes of Health and the U.S. National Multiple Sclerosis Society.

However, not everyone is convinced of the significance of this study.

Paul OConnor, director of the multiple sclerosis clinic at St. Michaels Hospital in Toronto, cautioned against concluding a cause-and-effect relationship between elevated IL-17 levels and a lack of response to medication.

While the theory may have merit, Dr. OConnor said, the study only looked at 26 patients and shouldnt be considered conclusive.

Its really a preliminary observation, Dr. OConnor said. We would need to do a much larger study to see whether or not this preliminary finding is actually verified.

Yet, most of the new MS research dollars may already be dedicated to getting to the bottom of Dr. Zambonis novel theory. Some studies are already under way, and the Multiple Sclerosis Society of Canada is expected to announce in coming months who will receive research funding in Canada.

Some Canadian patients excited by the possibility of curing their MS or eliminating symptoms have left the country to get the procedure in countries such as the United States and Poland.

But as more researchers investigate Dr. Zambonis theory, signs are emerging that it may not be as revolutionary as hoped, and could also present significant dangers to patients.

In February, researchers at the University of Buffalo released a study that showed as few as 56 per cent of MS patients they looked at had the blood vessel problem thought to cause the disorder. In addition, researchers found the blood vessel problem in about one-quarter of healthy people involved in the study.

I certainly would not recommend people get this treatment done until we figure out if theres real truth behind it, Dr. OConnor said.

The Wall Street Journal reported last week that Michael Dake, a vascular specialist at Stanford University, who had been performing the experimental procedure on MS patients, had to stop after one patient died of a brain hemorrhage and another had to have emergency surgery after a problem developed with a stent meant to open up a blood vessel.

Although the report noted there is no proven connection between stents and the patients death, the program was considered too risky and was shut down. Some patients had reported an improvement after the procedure.

Dr. Steinman said the case illustrates the dangers of embracing an experimental treatment before it has been properly evaluated and the problems that can occur when patients push for a procedure thats not yet adequately backed by evidence.Those of us that are trying to say Slow down, lets prove whether its right or wrong are sometimes cast as obstructionists, Dr. Steinman said. Is Zambonis breakthrough a big step? It remains to be seen.


Senior Member
Zomboni's treatment is getting more news coverage here. I saw two separate reports on CBC news world this week. One mentioned that a patient had a stent put in and it fell into their heart. :eek: Scary.

Also said that in some cases using a balloon to open up the veins is only had a short-term benefit. My husband and I both wondered could this not weaken the veins over time?


T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis

Nature Medicine | Article
T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis

Robert C Axtell, Brigit A de Jong, Katia Boniface, Laura F van der Voort, Roopa Bhat, Patrizia De Sarno, Rodrigo Naves, May Han, Franklin Zhong, Jim G Castellanos, Robert Mair, Athena Christakos, Ilan Kolkowitz, Liat Katz, Joep Killestein, Chris H Polman, Ren de Waal Malefyt, Lawrence Steinman & Chander Raman

Nature Medicine, Volume: 16, Pages: 406412 (2010)

Received 16 April 2009 Accepted 04 February 2010 Published online 28 March 2010


Interferon-β (IFN-β) is the major treatment for multiple sclerosis. However, this treatment is not always effective. Here we have found congruence in outcome between responses to IFN-β in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS). IFN-β was effective in reducing EAE symptoms induced by T helper type 1 (TH1) cells but exacerbated disease induced by TH17 cells. Effective treatment in TH1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes. In TH17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-β treatment still reduced IL-17 production without benefit. Both inhibition of IL-17 and induction of IL-10 depended on IFN-γ. In the absence of IFN-γ signaling, IFN-β therapy was ineffective in EAE. In RRMS patients, IFN-β nonresponders had higher IL-17F concentrations in serum compared to responders. Nonresponders had worse disease with more steroid usage and more relapses than did responders. Hence, IFN-β is proinflammatory in TH17-induced EAE. Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-β.


Senior Member
Thread resurection maybe this should be looked at again EAE
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Snow Leopard

South Australia
Natalizumab apparently has an effect on fatigue and cognition in MS patients (albeit open label trials), I'm curious to hear from anyone who has been administered Natalizumab?