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A bit more insight into the role of interferon gamma...



SOCS1

May 9, 2006 - Eurekalert - 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 10, 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 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.

http://www.eurekalert.org/pub_releases/ ... 050306.php

Dignan,

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.

By coincidence I was in correspondence with my 'good' neuro earlier this week and we spoke about the the stem cells projects which are to repair myelin. He was of the view that the success of such potential treatments would be limited because of the ongoing damage i.e. there is a need to stop the ongoing damage before attempting repair.

He is also of the view that the oligodendrocytes have also been damaged and that is why repair fails. Why oligodendrocytes are damaged is still to be established, but he referred to a "sick micro-environment" in the CNS.



Ian

Bromley,

Why can't I have a neuro like yours?????? Grrr.

Brock

Brock,

You need to be a pest. I soon realised that there are neurologists and neurologists. Some are still in the mindset of "we only diagnose" - "get on with it". The neuro who dx me was really a Parkinsons specialist with little interest in MS (or knowledge about it).

I then wrote to one of the UK neuros involved in cutting edge research (not the Avonex v Rebif stuff). He considered me too mild at the time for his trial but referred me for a second opinion to another leading MS doctor / researcher. I hit it off with the latter and correspond with him on a regular basis. Many of the opinions I post are his not mine (I am a history gradute / accountant). But I am also a reasonable judge of character and he is very driven to end this disease. He has strong views on the cause and has a view on promising treatments e.g. he thinks Rituxin holds real promise. His research also covers neuro-protection and repair so it's good to find out how things are going on these important areas.

Where possible I would always try to find a neuro with a specialism / sub-specialism in MS. Otherwise, you might be unlucky as I was with my first neuro who basically read out the report attached to the MRI.

Ian

Dear Bromley,

Have I understood your "good" neurologist, (surely this must be an oxymoron), correctly? He seems to be saying that if some revolutionary therapy arises which can relieve, undo or even reverse some of the damage to myelin and /or axons it wouldn't be worth doing because the underlying disease process continues.

This strikes me as grossly illogical and actually reminds me of the time I asked my gardener to cut a hedge, when he replied, "what's the point? It will only grow again". Surely it must be better to repeatedly repair any damage which occurs, in order to hold back deterioration until the cause(s) of MS can be identified.

Unfortunately for me, having had progressive MS for about 20 years, anything which could help prevent deterioration is a bit late in coming, so I must ask again the question I posted some time ago but to which nobody replied: supposing stem cells or some wonder drug really are able to regrow neural tissue, is there any research which suggests they may be able to repair old damage? I seem to recall reading on this website about a molecule which can break down scar tissue, but I can't remember the details. Any information on this would be much appreciated, (so long as it's information which doesn't contain the phrases, "which may one day lead to a treatment", or, "further research is required").

Dom.

Dignan,

As a fairly new member, I thank you for the intersting post on work being done to repair damage.

Bromley,
Nice to hear you have an interested Neuro. Given his knowledge of the disease and the studies being conducted, he still advised you to start the Avonexas the best course for the time being? I realize that he would advise on your specifics, but I'm interested to hear. I have been on the Avonex and off.


Cindy

Dom,

I think what my neuro is saying is that there is a sick environment in the CNS (perhaps a virus causing inflammation etc) that leads to the death of / damage to the cells which make myelin. He is of the opinion that there is not a problem with the number of these cells - the problem is that they are damaged by this sick environment. If new myelin making cells are introduced then they are going to be subject to the same sick environment. This appears sensible to me. It is the sick environment that needs to be addressed first.

The NMSS are funding projects looking at protection and repair. On repair they are looking at growth factors and molecules etc. This will be the big breakthrough when it comes - and with it comes the possibility of regaining lost functions. Some progress is being made - there was an article in the newspaper today about repairing nerve fibres relating to the eye (I'll post separately).



Cindy,

I wasn't keen to take any of the DMDs as they didn't appear that effective (on paper). He ran through the risks / benefits and his advice was 'do something' i.e. take one of them. He thought that Rebif had a slight edge (based upon his research), but not much to choose between the interferons. He thinks that Tysabri is more effective than the DMDs but that the risks have not been adequately defined.

I call him my 'good neuro' as (i) he is an MS specialist with stacks of research experience and is undertaking some cutting edge work (ii) he is really driven to conquer this disease (iii) he answers my questions even when they might appear very basic.

Ian

Thanks Bromley, I think I get it now. I was under the mistaken impression that the " sick environment" only reduced or impeded the functioning of any system which might be called upon to repair damage which, if that was the case, may have meant that regular boosting of that system would be enough to overcome any shortfall. If the environment is completely toxic and fatal to those cells however , then of course no amount of boosting will have any effect.

It seems you really have found a good neurologist! I'm sure he doesn't want to give away any secrets, but has he ever hinted at any optimism that he is close to understanding what may be going on?

Personally, since my diagnosis 20 years ago I've been left alone to get on with it -- no follow-up, no monitoring, no neurologist, no help. A couple of years ago, at my request, I did see a neurologist who flatly told me there was nothing that could be done for MS and there wouldn't be in the foreseeable future. I later saw an MS nurse who said that she had recently been to a neurological conference where the speakers had said that, with MS beginning to look like it's a number of different diseases, no one was getting anywhere and a lot of research was being wound up! Needless to say, I told her I didn't want to see her again.

So this Web site is a beacon of hope and informed opinion for me, with your contributions being outstanding. I'm at the end of my tether, but I think I can just keep going in the hope that your neurologist turns out not simply to be "good", but to be a bloody miracle worker!

Keep 'em coming!

Dom.

I have to comment on this interferon gamma.

There’s a hormone, DHEA, seemingly low in people with MS , that may have the potential to decrease it.

First this research found :

The activity of IFN-gamma-secreting cells, on the other hand, varied as a function of serum DHEA-S levels in pre-menopausal women (P < 0.0001). Similarly, the number of cells secreting IFN-gamma in men correlated with serum DHEA-S levels (P < 0.001)…. These results suggest that sex hormones may modulate cytokine production in vivo and contribute to gender-related differences in normal and pathological immune responses.

This abstract notes

DHEA also significantly reduced the mitogen-induced production of the proinflammatory cytokine interleukin-1 (IL-1) as well as the Th1 cytokines IL-2 and interferon-gamma (IFN-gamma).

Is it possible we have too much interferon gamma in part because we don’t have enough DHEA? It seems to me that could be a factor (or, not).

One of the really interesting things about DHEA IMO is that not only is it an immune modulator that may protect against viral and bacterial infections, but it also may protect against glutamate toxicity that’s been discussed in another thread. DHEA Protects Hippocampal Neurons

Because the release of glutamate has been implicated in the neural damage after cerebral ischemia and other neural insults, these results suggest that decreased DHEA levels may contribute significantly to the increased vulnerability of the aging or stressed human brain to such damage.

That's enough I think. The hormone corner wonders if not enough DHEA may be part of that "toxic CNS environment."

Take care everyone

Sharon

To pick up on two questions in this thread
(a) Bromley, did you neurologist consider copaxone//could you describe why he didn't recommend.
(b) Sharon, I apologize if I've asked this (pm doesn't seem to be working), but are you actively on a hormone treatment involving DHEA or other//if yes can you describe.
LJM

LJM,

My neuro ran through the interferons and considered that Rebif had a slight edge (I think this was confirmed in a trial). I get the impression that Copaxone works in a very different way and may offer more in terms of neuro-protection. But of course the price you pay is daily injections. If you look at a presentation I posted on combination treatments the neuro (Mike Boggild who seems to be well respected), has used Novantrone and then the patients take over with Copaxone (slight overlap of treatments when the Novatrone doses are reaching their limit).

The real frustrating thing with this disease is that no one knows if they are having any effect (on an individual basis). They talk about slowing down disability but who really knows how quick it would have been without? Most other treatment (for an infection, some cancers etc), they can say "you're over it". But this wretched disease doesn't play by the normal rules. Given this, I'm attracted to the more extreme treatments. When I need cheering up I look at the video I posted about the young woman with RR who took the risk with the bone marrow transplantation treatment. She was using crutches and leg braces but is now happily walking her dog! Isn't that what all of us want - to get back to how we were?

I'm sick of friends telling me how good our health service is - following operations for hernias, stents for heart problems etc. They get their life back and get on with it. The idea that you can have this vile disease for 30-40 years is the real killer. I remember my dad saying thank god it wasn't a brain tumour when I told him about the dx! Some days I'm not so sure I agree with him - some people at least get over them.

All the best

Ian

I agree with you Ian.

My mum received her driver's licence renewal today. She is 70 soon. Happily it could be completed with no disability record so she will likely get a renewal granted.

It made me wonder what I would be like at 70, if I ever got there.


J.

LJM, you asked:

Sharon, I apologize if I've asked this (pm doesn't seem to be working), but are you actively on a hormone treatment involving DHEA or other//if yes can you describe.

I'm implementing a basic “physiologically balanced and normal hormone levels” approach. With that, in my case, DHEA supplementation was not recommended even though my DHEA level was in fact low.

I have been trying to obtain normal and balanced levels of several hormones as a way to help manage my MS (and my hot flashes). My hormone level lab results (cortisol, DHEA, estriol, estradiol, progesterone and testosterone) form the basis of the compounded hormone prescriptions and doses I take. At the current time I am on 500 mg of progesterone (I had none of that) and 8 mg of estriol. The physician recommended that I not immediately supplement with DHEA even though it was low as the progesterone would probably increase it, i.e., the progesterone I was taking could cascade to DHEA and my DHEA level would increase that way. My cortisol (stress hormone) was high and my testosterone level was within normal range.

So, basically, I had my hormone levels tested and prescriptions recommended based on my lab results. After 3 months on the originally prescribed amounts, all my hormone levels were re-tested to determine if the “imbalances” were coming into balance (my progesterone still wasn’t so the dose was increased). Once I achieve relatively stable and balanced hormone levels, the recommendation is to have them tested annually to identify the need for any adjustments. I need to have them tested again so the prescriptions could in fact change. It’s all very individualized.

Now, for the “twist”, Yes, I am currently “self-medicating” (a definite no no) and taking 5mg. of time released DHEA at night to try and manage what I believe is Avonex induced depression. Clinical trials of DHEA and depression in the normal population indicated that it was useful. I’ve been doing that for about 2 weeks.

I hope this info addresses your question.

Ian—I remember I’m old enough to be your mother (so puleez don't remind me again because I haven’t forgotten) and I’m still optimistic and confident that there’s going to be tremendous progress in MS treatment well before you reach my age. Jaded—I’m close to 60 and still driving (dangerously too) .

Take care everyone

Sharon

Sharon, I can't resist. I know you'll take this in the right way--remember: insulin is a hormone too.

In one of your next blood tests for hormones, ask to include a fasting serum insulin test. I'll bet the result would be 10 or above (below 10 is best, but my suspicion is that it is high for folks with MS).

Also remember that I respect your search and, though it may lead in a different direction (hormones), who can say which path will lead to the answer? I feel fortunate to be with you in a group that's searching.

Lynda Carol

I'm glad you can't resist. I'll try to remember insulin is a hormone, it's not one that I've read anything about though so I'm counting on you and others for info on that front. I plan to ask for that fasting serum insulin test when I see my primary care physician.

As for a path to an answer, I think it's going to take lots of paths. The role of sex/steroid hormones, if any, in the pathogenesis of MS remains totally unknown but their neuroprotective properties have captured my interest. It's an area of research that I think has generally been ignored for way too long so I persist

Take care

Sharon