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Hi Loobie,

Personally, when I think of neurodegeneration, I don't imagine axons, myelin, or oligodendrocytes actually being attacked by a rogue immune system, more that they decay and die off due to some other mechanism -- possibly premature apoptosis -- that leads to the overall loss of brain volume typical of MS.
This may be the triggering factor that causes the immune system to "Go Bad", and activate auto reactive T-cells in an over enthusiastic response. Tovaxin is aimed at getting rid of these T-cells by vaccinating against them, and looks like is going to be pretty successful in doing that. Whether neurodegeneration or T cells are the prime mover in MS, however, remains open to question. If both are present in the MS brain though, I should have thought that removing one of them can only help.

I'm sorry if that answer isn't very comprehensive or satisfactory -- I'm having a bit of a "woolly Brain Day" -- but it did make me remember something: when I was a kid, one of the "facts that everybody knows" was that we all lose 10,000 brain cells a day. I never understood if that was through apoptosis, short telomeres, or what, but it does paint a picture of a brain being able to maintain itself which seems sadly lacking in MS.

Loobie, congratulations and thanks for getting on this trial -- I hope Tovaxin does prove to be "the one" for you and that you're blazing a trail to a better future for all of us,

Dom.

Thanks for the answers. Insight was what I was really after since I know no one really has the answer to my specific question...at least not yet! Anyway, thanks for taking the time to respond to my question. My trial has been going fairly well. I got my last monthly injection last month, so my next one (the booster) won't be for four months I believe. Then I find out if I got the goods or not in November. I appreciate your responses.

Lew

Loobie wrote: My question is this. It sounds to me that regardless of whether the "bad cells" are attacking myelin first or axons or whatever first, could it be assumed that the Tovaxin approach to neutralize the damaging cells has potential to work if either condition were present?

Hi Lew,
Although they've put a lot of effort into perfecting the technique, all Tovaxin has ever been designed and intended to do is remove myelin reactive T cells (myelin attacking) from circulation. There is no reason to think that it does or could do anything else.

If Tovaxin is as effective as is being stated it would seem to prove that the traditional theory is true (myelin is attacked first which leaves the axons vulnerable) because if the axons were first to be attacked, saving the myelin wouldn't be very useful.

Personally, when I think of neurodegeneration, I don't imagine axons, myelin, or oligodendrocytes actually being attacked by a rogue immune system, more that they decay and die off due to some other mechanism -- possibly premature apoptosis -- that leads to the overall loss of brain volume typical of MS.

Hi Dom,
The idea behind the word "atophy" is that something which atrophies had been part of a system which has been isolated and left to wither.

As with the poor example I gave of my brother's broken arm the other day, the cause of isolation can involve lack of use, lack of sustenance or in this case possibly the atrophy is due to lack of use because it has been isolated from the electrical pathway because of axon loss farther up the circuit. Really, the same as a light bulb is no longer part of the circuit when the switch is turned off. If a light bulb were tissue it would wither from lack of use. Therein lies part of the reason I feel brain atrophy isn't entirely irreversible.

Interestingly, not long after the invent of the MRI, researchers must have been desperate to find a use for it because I read of a study in which someone did a baseline MRI on subjects and then had them intensely concentrate on artistic endeavors for long periods. Later MRI showed the part of the brain responsible for artistic endeavors grew in size.

To me, that seems to mean that if those faulty circuits could be reconnected, and we've all seen hopeful research in that regard recently, it seems that those "atrophied" areas of the brain could come back with use.

I'm not saying it's going to be all the original axons and myelin but where did all the extra axons and myelin come from in those test subjects which was necessary for the enlargement? That had to have involved more than their brain lobes simply swelling.

Sadly, I've searched and searched for reference of that experiment since then but I read it long before I had the internet so it must have been in a science magazine. The only science magazines I've ever subscribed to were "Omni" and "Discover". If anyone ever finds it, I'd love to read it again.

Bob

TwistedHelix wrote:Tovaxin is aimed at getting rid of these T-cells by vaccinating against them, and looks like is going to be pretty successful in doing that. Whether neurodegeneration or T cells are the prime mover in MS, however, remains open to question. If both are present in the MS brain though, I should have thought that removing one of them can only help.

I think Dom summarized reasons to try Tovaxin very well. If it turns out to be a safe and well tolerated treatment, using it even for longer periods of time might not do any harm. And trying to protect the myelin may always be a good idea, no matter what the pathology of this disease turns out to be ;-)

It is good to remember though, that there is the chance that inflammation may be (at least partly) neuroprotective, but I won't go into that anymore.

Lyon wrote:If Tovaxin is as effective as is being stated it would seem to prove that the traditional theory is true (myelin is attacked first which leaves the axons vulnerable) because if the axons were first to be attacked, saving the myelin wouldn't be very useful.

Of course saving the myelin could be useful, even if the axons were injured first. If the slow degeneration process had started much earlier without any clear clinical signs, and there were already less axons, perhaps only a small temporary injury in the protective myelin sheath could cause the first clinical symptoms. Actually, that way one could even explain the rapid changes between relapses and complite remissions seen sometimes in early RRMS.

Btw, in the first phase II trial Tovaxin reduced the amount of relapses by 92%. It is a lot, but not enough to prove any theory valid or wrong. Especially since the correlation between relapse rate and progression of permanent disability hasn't been that strong.

-finn

I think this debate is going to run and run. It's a bit like the ongoing debate about healthy eating, with each piece of research seeming to contradict the last until we are all completely confused, (see my recent post, "relapses DO contribute to progression", which appears to support the "old fashioned " standard view of MS relapses).

Hi Bob,
Your definition of atrophy fits in with the research which found that the impulses surging through an axon are part of the signalling pathway which calls in oligodendrocytes to myelinate, and support, the axon. The problem is, why does the axon reduce, and then stop, these impulses in the first place? This may be where the gene CNP comes in which, as I've described before, it's expressed in normal appearing myelin but causes the axon inside to decay and die. Spingolipids may play a part here as they have a role in cell growth and death, and Sphingomyelin forms the outer leaflet membrane as the barrier to the extracellular fluid. If the axon inside can wither away while it remains encased in myelin, this atrophy could go on for years, unnoticed . I'm sure I read somewhere that Sphingonlipids also form part of the membrane at the synapse , so if they had anything to do with the sodium/potassium ion pump, they might be part of the mechanism by which unmyelinated Grey matter axons die through imbalance and excitotoxicity. As I said, I can't remember where I read this, so it could all have been a horrible dream!

Hi Finn,

I wanted to reply directly to your posts, (which are always stimulating, well-informed and interesting), but a), I feel as if I've waffled on enough and b), my speech recognition programme always causes havoc when I try to write a post, so I can't scroll down to see what you've written!

B T W -- I haven't seen Omni for years... I used to love it!

Dom.

TwistedHelix wrote:Your definition of atrophy fits in with the research which found that the impulses surging through an axon are part of the signalling pathway which calls in oligodendrocytes to myelinate, and support, the axon. The problem is, why does the axon reduce, and then stop, these impulses in the first place?

Hi Dom,
I'm not sure what your above statement means. The researchers in that study are speculating that myelinsation is an ongoing process and instead of actual "demyelinisation", the signal to myelinate gets interrupted and eventually the myelin just wears thin?

Something came to mind just now. Someone mentioned that there is reason to think that the axons die first. Someone else mentioned there is reason to believe that in ms the axons become surrounded in a "toxic environment".

We are used to seeing pictures of short strips of myelin in ms representations but in reality axons can be very long.

In the mass.....the jumble of axons it seems impossible that researchers would ever be able to see the entire axon. Not that this puts either theory (axon death first/myelin death first) at advantage, but really how do researchers really know what has happened at the other end of the axon they are studying?

In other words, if I were looking through a microscope at a decaying axon surrounded in good myelin, or an axon in a toxic environment...how could I be certain that at the other end of that axon, myelin loss hadn't already allowed the axon to die? How would I know that what I was viewing on my end of the axon wasn't really the "correct" function of the immune system in progress...cleaning up useless and dead material?
Bob

Dom,
too bad the software you're using doesn't work the way it should at the moment. It's been a real pleasure to read your posts. Even a foreigner like me, who doesn't use English that much, is able to tell that you're verbally extremely gifted.

I'm happy to be able to think and post on a "meta level", but the way you can go into details is remarkable. You find and connect different biological processes so well.

Keep up the good work, and be well.

-finn

First of all, and just to prove I don't know what the hell I'm talking about, I made a mistake in the previous post: I didn't mean potassium and sodium; I should have said calcium -- I woke up at 3 o'clock in the morning realising this, which just goes to show that even my dreams are boring!

Finn, I take what you said as a real compliment, especially coming from someone who obviously has an excellent understanding in this field. And as for your English: I would NEVER have guessed you weren't a native English speaker... I'd always assumed you were an English person living in Finland!
I don't have any specialist knowledge about the nervous system: I just do exactly as you guessed; just take various bits of information about research and piece together the ones that seem to fit. A specialist would probably demolish anything I have to say in a few seconds.

Bob, I think what the research was getting at was maintenance. As you know, every cell and structure in the body is regularly repaired, maintained and replaced, and in the case of axons the strength, and possibly frequency, of electrical impulses seems to be a crucial signal to the body to continue that maintenance. If those impulses weaken and stop, so will any effort to repair and tissue, (both axons and myelin), will wither away.
Of course, this still doesn't answer the question about which comes first: myelin damage or axonal decay, or indeed what is the root cause of these events, but I suppose if we knew that this website could close down
That was a really good point you made about seeing the whole length of an axon -- a bit like trying to see an entire piece of spaghetti in a plate full of bolognese. It made me think: the discovery that unmyelinated Grey matter axons also die in MS made everyone revise the theory that demyelination was the key factor. But what if those axons are only kept alive by the constant stimulation they are supposed to receive from their myelinated neighbours? Demyelination occurs, this weakens the "please keep me maintained" electrical signal in every axon down the line , and we see atrophy in both grey and white matter .

I'm just thinking out loud here as I'm writing, and haven't really thought this through, but my head's spinning so I think I'd better go and concentrate on something simple like quantum physics.

Bob, thanks again for the information you sent me: you've definitely got me convinced about helminths!

Dom.[/i]

TwistedHelix wrote: Bob, thanks again for the information you sent me: you've definitely got me convinced about helminths! Dom.[/i]

Hi Dom,
It's funny that you mention waking up at 3 am with the correct answer in your mind. In my experience that's exactly how the correct thoughts happen. Something about sleep helps to separate the wheat from the chaft (sensible thoughts from the clutter).

Regarding the loss of parasites from the populations of the "developed" world....I've been reading about that stuff for five years and the more I read, the more convinced I become. The fact that nothing else about ms has ever made any sense only seems to add to the validity of this.....what is starting to be referred to as the loss of "evolutionary normal" conditions.

In all the time I've dwelled on this situation, the only "dissapointment" I've run into is that it involves the most completely disgusting creature ever known to man.

It really couldn't be a more unfortunate situation. Then again, in the world of ms who would expect any different?

Bob

Hi Finn,

It's good to see you back and posting again. I can certainly follow your arguments, however they are abductive reasoning, i.e. one chooses the hypothesis which would, if true, best explain the relevant evidence. For the arguments to gain credence there must be empirical evidence to support them. Whilst the findings of say, Prineas and Barnett would appear to provide empirical evidence there are other perfectly good explanations for them.

On the other hand there is good empirical evidence that altering the immune system early in the disease course has a beneficial effect. To take myself as a case in point, in the 2 years prior to Campath treatment I prgressed approx. 3 points on the EDSS scale. In the two years post treatment I have regained approx. 3 EDSS points. Not conclusive evidence by any means, I may be a statistical anomaly. However given that this appears to be the norm with Campath treatment rather than the exception, one has to lend a certain weight to the results that cannot be given to the purely abductive hypothesis.

Does this prove or disprove the auto-immune theory? Absolutely not. There is nothing to say that I wont progress rapidly at some point in the future. However, at this point in time, given all the available evidence and combining that with personal experience I have to say I am firmly in the 'is auto-immune' camp.

All the best.

Robin

raven,
thanks for your comments. It was nice to hear you're doing fine after Campath treatment.

I don't know how closely you have followed this thread, but earlier I wrote that "clinical relapses and reverseable disability are caused by demyelination driven by inflammation". You seem to be a living example of it. I'd personally say there are only few reliable examples that altering the immune system early in the disease course has had a long lasting beneficial effect (months, maybe even years), but there's also pathological and imaging evidence that neurodegeneration has progressed even after immunosuppression and without inflammation already in the earliest clinical stages of MS. So the questions are, will the beneficial effect of modifying the immune system be enough to "stop the disease in its tracks", and will the effect last? Would it all really depend on the timing of the treatment? Does preventing inflammation as early as possible halt axonal degeneration? You're one of those who could help giving us answers so good luck with the trial.

It's been fun to speculate with you guys, but I suppose I've done it enough already. Just to summarize some of my thoughts (and maybe also this thread) I'd like to quote an abstract I noticed on the Accelerated Cure's website last friday:

"Understanding the disease processes underlying multiple sclerosis is crucial to optimise treatment and to develop new therapeutic entities. Our understanding has been dominated by the inflammatory model of multiple sclerosis. More recently, a neurodegenerative model of the disease process has been developed which complements the inflammatory hypothesis in understanding the disease process and suggests a way forward to develop more effective treatments. Histopathological studies have shown that the early disease stage is characterised by acute inflammatory attacks, with T-cell infiltration, gliosis and acute demyelination. Axonal damage is also generally visible at this stage. In late-stage disease, continuing slow axonal damage may remain in the absence of signs of inflammation.

Inflammation may not always have a deleterious outcome in multiple sclerosis since the release of growth factors from immune cells may protect neurones against axonal damage or facilitate axonal repair. The processes underlying lesion development appear to be heterogeneous, in some cases being driven by immune-cell mediated gliotoxicity and in others by primary gliopathy. Remyelination occurs to differing degrees in different individuals, and the reasons for this heterogeneity are poorly understood. Finally, the antigens that trigger the autoimmune response have not been characterised and may differ between patients. Candidates include myelin proteins, oligodendrocyte precursor proteins and axonal constituents.

These different aspects of pathophysiology need to be brought together in a unified hypothesis of disease, but current knowledge does not permit such a hypothesis to be proposed."

Be well.

-finn

raven wrote:In the two years post treatment I have regained approx. 3 EDSS points. Not conclusive evidence by any means, I may be a statistical anomaly. However given that this appears to be the norm with Campath treatment rather than the exception, one has to lend a certain weight to the results that cannot be given to the purely abductive hypothesis.

Hi Robin,
Good to see that you still "haunt" this site occasionally!

You and I have talked about campath before and it's obvious that you're very aware that only time will tell whether ms is out of your life forever. Obviously dying of something else is the only way to ever be sure.

On the other hand it would be foolish to ignore the fact that in the last few years Campath, HDC and Tovaxin seem to have done something which constitutes a major change from the long history of ms research. For the first time these things seem to obviously, directly and consistantly alter the disease.

Regardless of the treatment it's inevitable that the results are going to have to pass the test of time, but as you and others can attest, even in that regard campath seems to be off to a good start.

The successes of Campath aren't contrary to any of my pet theories. Even if it was I would hope to be big enough to want to see ms fade into oblivion more than wanting to see my pet theories proven correct.

I can't tell you how happy I am that you've gotten your life back. It remains to be seen how long it will last but I'm glad to hear that things are still positive at two years and counting.

Bob

Finn,

Attached is an interesting answer by Dr Freedman. His answer makes reference to good and bad inflammation and an inbalance between the two. Interestingly, for those participants in the Bone Marrow Transplantation study whiuch Dr Freedman is overseeing, when the immune system recovers, only the good inflammation comes back!

All the best

Ian


http://www.msanswers.ca/QuestionView.aspx?L=2&QID=220

Ian,
thanks for the interesting piece of information. What makes it even more interesting is that Dr Freedman appears to be one of the co-authors of this recent paper:

Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis.

Btw, I'd really like to know how he has been able to tell the difference between "good" and "bad" inflammation in CNS.

Be well.

-finn

Finn,

Thanks for posting that summary of one kind of stem cell therapy for MS.

One of these days, the researchers are going to abandon the theory that MS is an auto-immune disease and that it is the patient's immune system which is reacting to some far more sinister "process" that is taking place within the brain. When that happens, perhaps there will be some real progress made in finding the answer.

Harry