Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby dignan » Wed Mar 14, 2007 1:36 pm

Finn, I think you point out the extreme difference between responders and non-responders to this treatment. Responders: no progression, no relapses, no lesions. Non-responders: dead.

Now if only they can figure out why some people do well and other people die, we'd be getting somewhere. It would seem that it isn't the actual procedure that kills people any more as I don't believe any MS patients have died from autologous stem cell transplant complications for the last few years.
User avatar
dignan
Family Elder
 
Posts: 1608
Joined: Wed Aug 11, 2004 3:00 pm

Advertisement

Postby finn » Fri Mar 16, 2007 3:27 am

dignan,

dignan wrote:Finn, I think you point out the extreme difference between responders and non-responders to this treatment. Responders: no progression, no relapses, no lesions. Non-responders: dead.

Yes, that's one way to interpret the study. But I'd say its results give room to other interpretations, too.

In the study researchers analyzed 53 white matter lesions taken from autopsy material from 5 MS patients who had received high dose chemo therapy and bone marrow transplant. They found very little immune system activity (only few T cells, no B cells), but ongoing demyelination and axonal degeneration. Without biopsies taken from them we just don't know if the pathological state would be the same in the brain of those patients who responded clinically well to the treatment. So the key question remains to be answered, is halting demyelination caused by inflammation really able to stop axonal degeneration for good (at any stage of the disease process)?

dignan wrote:Now if only they can figure out why some people do well and other people die, we'd be getting somewhere. It would seem that it isn't the actual procedure that kills people any more as I don't believe any MS patients have died from autologous stem cell transplant complications for the last few years.

I'd like to think that researchers already have some kind of idea why some people may die shortly after the procedure. Even though no MS patients have died lately, autologous stem cell transplant is a risky treatment. As far as I remember, when used as a cancer treatment its mortality rate has been around 3 percent.

Harry,

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

You're welcome. I suppose it is just about the only kind of stem cell therapy studied in MS at the moment. I'm afraid I have my doubts about it for two reasons:

1. I don't understand the need for cell transplant. Similar clinical results have been achieved with high dose chemo therapy alone.

2. "Autologous" means "using patient's own tissue". If I have understood it right, when used as a cancer treatment, autologous bone marrow transplant may be used only to buy some more time while waiting for the matching tissue for allogeneic transplant. In many cases the only "cure" for cancer with long lasting effect has been allogeneic stem cell transplant, where cells come from a matching donor.

HarryZ wrote: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.

In the light of my current knowledge I tend to think the same way you do. On the other hand, demyelination caused by inflammation seems to have an impact on the clinical course of relapsive forms of the disease. I know I sound like a broken record, but I just need to ask the following question again: Which comes first, demyelination caused by inflammation or axonal degeneration?

These are complicated issues. It's been interesting to follow the change in the way mainstream researchers see the pathology of MS. Instead of new autoimmune theories, now we can read more open minded comments about it. Actually, Dom just posted one a while ago.

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
User avatar
finn
Contributing Author
 
Posts: 289
Joined: Wed Mar 17, 2004 4:00 pm
Location: Finland

Postby HarryZ » Fri Mar 16, 2007 6:47 am

Hi Finn,

These are complicated issues. It's been interesting to follow the change in the way mainstream researchers see the pathology of MS. Instead of new autoimmune theories, now we can read more open minded comments about it. Actually, Dom just posted one a while ago.

Be well.

-finn


Yes, things certainly are starting to change thanks to some discoveries in the past couple of years. At least other possibilities are being explored.

I am also of the same thought as you when it comes to stem cell therapies for MS patients. There was a lot of excitement at first when stem cells were being used. Unfortunately initial positive results were giving way to a return of symptoms and disease progression.

Until the researchers find out just what is initially causing MS and the process, the therapies of today are only temporarily getting in the way of the disease marching on. Hopefully soon some doc will stumble upon the answer.

Harry
User avatar
HarryZ
Family Elder
 
Posts: 2442
Joined: Tue May 25, 2004 3:00 pm
Location: London, ON, Canada

Postby Lyon » Fri Mar 16, 2007 9:17 am

HarryZ wrote: 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.
Hi Harry,
Again, I'm not entrenched deeply enough to take sides (although in my case the facts point towards autoimmune) but this is another case of using inconclusive evidence to bolster your convictions. Example, this is taken from the autologous haematopoietic stem cell study that Finn linked to
Clinical progression after HSCT has not been documented in the patients studied here; this may be due to the fact that survival times were 2 months or less in three of the five cases presented here.
I have no loyalties and will sway whichever way the facts point....but the "fact" part is kind of important.
Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 3:00 pm

Postby HarryZ » Fri Mar 16, 2007 9:38 am

Hi Bob,

The big problem is that nobody, regardless of which side of the fence they sit (auto-immune vs other cause), can prove their theories.

I've followed the auto-immune theories for decades now and where has that lead MS research...no known cause and certainly no decent treatments. Will looking down another path bring us closer to the answer any time soon? Let's just say that I doubt it could be any worse than following the auto-immune route for the last 40 years!!

Take care.

Harry
User avatar
HarryZ
Family Elder
 
Posts: 2442
Joined: Tue May 25, 2004 3:00 pm
Location: London, ON, Canada

Postby Lyon » Fri Mar 16, 2007 2:10 pm

HarryZ wrote: I've followed the auto-immune theories for decades now and where has that lead MS research...no known cause and certainly no decent treatments. Will looking down another path bring us closer to the answer any time soon? Let's just say that I doubt it could be any worse than following the auto-immune route for the last 40 years!!
Hi Harry,
Of course there is the factor that I just like to harrass you to consider!

It's always seemed suspicious that the autoimmune/not autoimmune issue is so contentious with us laymen, because it also happens to be the only possible wrong turn in the history of MS research which involves a simple "right/wrong" answer as compared to the rest which involve multiple choice with an infinite number of variables. It's too easy to say that "after all these years of research we should have the answers by now so autoimmune was obviously the wrong turn". I also want to label the wrong turn but I don't see the benefit in substituting one wrong turn for another.

The auto/not autoimmune issue is the easiest possibility to argue, but is it the right "wrong" turn?

If you got your way and all the world's MS researchers decided tomorrow that MS is not autoimmune, would that drastically change the direction of research?

Regardless of whether or not MS is autoimmune, researchers respond to what they see, that's all they can do. At least to my way of thinking, it doesn't matter whether MS is considered autoimmune or not.

If I'm wrong I honestly would like to be enlightened. What specific alternate direction would you like researchers to head? What specific aspects of non autoimmune would you like to see researched?

Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 3:00 pm

Postby Frank » Fri Mar 16, 2007 3:54 pm

Hello everyone,

I wanted to add my view on the basic statements of the autoimmune theory:

I refer to an explanation given for on various locations and for example here:
UCSF Multiple Sclerosis Center FAQ section "The Role of the Immune Systems"

My strongest objection is, that the basic statements of that theory are far too vague to only follow this track. Autoimmunity argues that:
An unknown pathogen (a virus or bacteria) causes T-Cells to go in an active state. Some of these activated T-Cells cross the BBB.
In the referenced model they do not say there is anything wrong with the permeabiliy of BBB but it is considerd as a usual process that T-Cells can cross BBB.

Why do they get to the CNS at all? Is there something wrong in this location? T-Cells have to be guided in some way to reach their designated target.

After entering the CNS coincidently?! they are reactivated by microglia which present mylin peptides on their MHC; to the T-Cells this peptide looks somehow the same as the pathogen that originally activated them.
This causes the T-Cells to attack the myelin sheath.

The only thing I know that has been evidently found so far are tissue samples which contain different types of immune cells.
Thats not really convincing, and certainly does not justify to leave other models aside.
I'm sure all of you know the 2004 austalien study at ThisIsMS
by Dr. Barnet who found, that in some (the earleies state?) lesions oligodendrocyt death occured while immune-cells were abscent.
So even this one thing autoimmunity had, could be seen in a different light.

In addition, autologous stem cell transplant is evident not to stop disease progression (at least in late states of MS) and there are still new lesions forming within the CNS but with only very few immune cells on-site.

On the other hand many studies found significant increased virus (e.g. HHV-6) and bactia load in different samples (Blood, serum, CSF) - references can be added if someone is interested in.

The only one human clinical trial I could find that targets virus in MS used valacyclovir to fight HHV-6:
pubmed
It did not find statisticly significant difference between placebo and verum.

Thats not too surprising, as this study states acyclovir is not potent to fight HHV-6 infection in glia cells. Its somehow frustrating they didnt even take the time to evaluate what drug to choose:
pubmed

From my personal point of view, a secondary immunesystem involvement, as garbage collector, after some pathogen causes cell death in the CNS seem pretty rational, while the classic autoimmune approach lacks a continuous concept, especially at the beginning of the theory.

At least it would be reasonable to have some serious efforts on the infections in MS. Potential drugs would be available and do only cost a fractional amount of standart MS regimes.

Another important point about autoimmunity I find hard to explain, is described in this thread:
ThisIsMS Thread: Why do relpases go
Its basic question is: Why would the immune-system stop its attack if the pathogen (Mylin) is still present.
Maybe the threads title was not the best wording :oops: .

Greets
--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
Frank
Family Elder
 
Posts: 542
Joined: Wed Jan 03, 2007 4:00 pm
Location: Germany

Postby Lyon » Fri Mar 16, 2007 4:10 pm

Frank wrote:ThisIsMS Thread: Why do relpases go
Its basic question is: Why would the immune-system stop its attack if the pathogen (Mylin) is still present.
Maybe the threads title was not the best wording :oops:
Hi Frank,
Maybe not the best wording but I don't think it was terrible either.

That's one of the million dollar questions about MS. How could anyone respond because no one knows and it's hard to even speculate on that one (if I'm correct and you're asking what the reason is for the relapsing/remitting aspect).
Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 3:00 pm

Postby HarryZ » Fri Mar 16, 2007 8:43 pm

Hi Bob,

The auto-immune theory with MS got started decades ago when researchers injected a dog's myelin with an antibody. The immune system attacked this foreign object and a conclusion was made that myelin destruction must be immune system related.

For years the scientists have followed this path almost exclusively and a few drug companies jumped on the band wagon and ensured it pretty much remained on this course. The MS scientific community, with large research grants from these companies, pretty much put all their resources into the same line of thinking. Up until a few years ago, there was only the interferon drugs that came out of this and we know how minimally effective they are. I'll never forget my wife's neurologist telling her back in 2000 that the CRAB drugs were very disappointing, they didn't do what they expected them to do and an answer to MS appeared to be so elusive. And this guy was involved in several clinical trials for these very drugs.

Back in the late 40's and early 50's, Dr. Hinton Jonez treated thousands of MS patients with IV histamine. Apparently about 80% of his patients showed improvement in their MS symptoms. When he died suddenly in the early 50's, his clinic closed, the research stopped and his work with histamine was virtually wiped off the face of the earth. Back then Jonez was at odds with the established MS medical community so it isn't surprising that his work died along with him.

Fast forward to Dr. P. O. Behan's Pathogenesis of MS about 6 years ago which highly questioned the auto-immune theory and MS's abysmal record of research.

Then we have Drs. Prineas and Barnett's findings with their autopsies on the brain lesions showing no evidence of immune system activity. I don't find their discovery surprising but what I can't understand is why it took until just a couple of years ago for this discovery to take place. Surely this kind of finding should have come up somewhere in previous autopsies but perhaps nobody was looking for it. Was this another result of the auto-immune theory keeping the researchers from looking at other ideas?

You asked me what direction of research I would have chosen. Not being a researcher I really don't know but what I do feel strongly about is that the fixation on the auto-immune theory has kept other possible avenues shut for a very long time. Perhaps someone would have explored Jonez's success with histamine or looked more closely at antibiotics which is starting to happen.

That's all I feel is that after watching this work go on for 40+ years, MS patients have been given little if anything to celebrate about. Symptom control is much better than what it was but beyond that, not much else. Powerful anti-cancer drugs being tested on MS patients, stem cell work designed to re-start the person's immune system, monoclonal antibodies to prevent the immune system from working normally and oral interferons are still catching the headlines. I really wonder if much has changed!!

Take care.

Harry
User avatar
HarryZ
Family Elder
 
Posts: 2442
Joined: Tue May 25, 2004 3:00 pm
Location: London, ON, Canada

Postby Lyon » Fri Mar 16, 2007 9:17 pm

HarryZ wrote: That's all I feel is that after watching this work go on for 40+ years, MS patients have been given little if anything to celebrate about. Symptom control is much better than what it was but beyond that, not much else. Powerful anti-cancer drugs being tested on MS patients, stem cell work designed to re-start the person's immune system, monoclonal antibodies to prevent the immune system from working normally and oral interferons are still catching the headlines. I really wonder if much has changed!!
Hi Harry,
Don't get me wrong, I share a lot of your concerns, but despite everything else it's hard to overlook one thing you mentioned, the seemingly obvious alteration of the disease course by resetting the immune system over the long term if not permenantly. How is that possible if it's not slapping the immune system back in line, and if slapping the immune system back in line has such an effect doesn't that have to mean that the immune system was out of line in the first place?

There is a lot about the autoimmune theory that I can't shape into a complete picture of MS. In a lot of ways life would be easier for me if there weren't reason to believe that MS is autoimmune but there are just enough smatterings of undeniable proofs which make it too hard NOT to believe it.

I think Finn mentioned earlier that none of us should be too engrained with any certain theories because in the end the truth of the matter is probably going to encompass a mixture of factors which we can't even envision at this point.
Bob
Lyon
Family Elder
 
Posts: 6063
Joined: Wed May 03, 2006 3:00 pm

Postby Frank » Sat Mar 17, 2007 1:41 am

Hello Bob,

I'm a bit sceptic when looking at recent success, postulated using new MS drugs (like Tovaxin, HDC, AST, BHT-3009 etc).

All of these studys show impressive results on dissease progression measured by T2 lesions on MRI.
But as we all had to learn damage in MS occurs throuout all part of the brain (grey matter, normal appearing white matter, axons, atrophy).

Most of the trials are open labled, and therefor prone bias and manipulation on any level (patients, doctors - evaluation of relapse and EDSS, statistics etc.).

Some of the new drugs show an effect on EDSS (stabilisation or even improvement) over some period of time, mostly not longer than 2 years.
A canadian study involving 2.800 patients found 40 years after diagnosis "only" 25% where forces to use a wheelchair.
There has been a Study looking at a cohort of around 160 MS patients for 10 years - 1991 to 2001. It found that over this period the average EDSS increase was only 1.0 .
So the question is whether 2 years are sufficient to distinguish between reversible short term clinical exacerbation and irreversible long term disability.

When it comes to autologous stem cell transplantation(AST) it has been shown that brain atrophy advances 10 TIMES faster than befor transplant!
Taking in regard, that atrophy is considered to be one of the most significant factor for irreversible long term disability, makes me not too optimistio about AST on the long run.
The fact that this atrophy is thought to be due to chemotoxicity, arisis the question as whether high dose cyclophosphamide(HDC) will lead to similar damage within the CNS.

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
Frank
Family Elder
 
Posts: 542
Joined: Wed Jan 03, 2007 4:00 pm
Location: Germany

Postby finn » Sat Mar 17, 2007 3:22 am

Frank,
thanks for your posts. IMO, they've been a great combination of opinions and hard data.

I agree with you, one has a good reason to be sceptical when evaluating the data supporting the ability of a treatment to halt the proggression of permanent disability. Like you wrote, two years may be too short period of time to evaluate it. Actually, here's another study supporting your point of view. Quote:

"More than 50% of CIS/RRMS patients who fulfil the current trial definition of confirmed disability progression subsequently improve back to baseline. However, the time to improvement can be substantially longer than the 2-year duration of most therapeutic trials. We caution that prolonged relapse-associated disability is a major confounder in the assessment of permanent disability progression in the relapsing-remitting phase of MS."

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
User avatar
finn
Contributing Author
 
Posts: 289
Joined: Wed Mar 17, 2004 4:00 pm
Location: Finland

Postby bromley » Sat Mar 17, 2007 6:45 am

Finn / Harry,

I think the tide is turning with regard to MS research - possibly reflecting the better technology available and a recognition that the first therapies for MS have not been as effective as hoped - in terms of stopping / radically slowing down the progression of the disease. The change can be seen in the subjects to be covered at MS conferences this year - in particular the focus on neuro-protection which has been gaining more interest in the past few years and treatments are currently in trial. There is also more focus on repair - although we are probably quite a few years away from seeing real progress in this area.

http://www.thisisms.com/ftopict-3765.html


Research since the late 1990s has shown that MS is a neuro-degenerative disease (although whether inflammation causes it, or is a response to it, has still to be pinned down). Recent research has shown that the disease is a global disease of the CNS rather than a focal disease (i.e. more than just lesions).

Much research is focussing on the role of pathogens, including viruses such as EBV. Whether an infectious pathogen just triggers off the immune system response or is the reason for the on-going immune system response has still to be pinned down. But viruses are being examined in many types of so-called "auto-immune" diseases such as diabetes. And with PML, a more vicious demyelinating disease, the JC virus (dormant in the majority of people) is reactivated and the reason for the devastating damage. I don't think PML is described as auto-immune, but it is clear that the immune system does the damage in its efforts to control / clear the virus.

I know Mr Z isn't a big fan of the monoclonal anti-bodies (although no-one complains when they are used to treat cancer), but the mono-clonals being trialled may shed more light on this disease. Campath is very effective at whacking the T cells and B cells, thereby dramatically reducing relapses and allowing the body to repair "reversible" damage, but may also promote some repair - see the research undertaken by once of the neuros overseeing the Campath trial:

Multiple sclerosis is a disease in which patients develop inflammation in the brain resulting in damage to nerves. Campath-1H is a known treatment for multiple sclerosis that reduces inflammation. New research suggests this treatment may also help repair damaged nerves. This project involves investigating the function of white blood cells from patients treated with Campath-1H. A series of laboratory techniques will be used to determine if the cells of treated patients work to enhance nerve growth. By clarifying the effect of Campath-1H on nerve growth and repair, this work will contribute to the development of future treatments for multiple sclerosis.



The EBV virus once someone has been infected stays with you for life (in B cells). It is the B cells that are dramatically reduced by Rituxan. This is one of the few drugs that is being trialled for PP MS - where inflammation plays much less of a role (compared with RR). I hope the outcome of this trial will show some positive results.

Dacluzimab is another mono-clonal in trial. Early work pointed to an unexpected mode of working - changing the type of T cell (from "bad" to "good").

MS research is changing its focus and the many trials underway will add to the knowledge. It may be that it will be possible to protect the nervous system before the researchers fully understand what is causing the damage. I'll take that when it comes. I'll also take the treatments that reverse "reverseable" disability.

Let's hope that further advances are reported this year.

Ian
User avatar
bromley
Family Elder
 
Posts: 1887
Joined: Fri Sep 10, 2004 3:00 pm

Postby HarryZ » Sat Mar 17, 2007 7:04 am

Hi Bob,

Don't get me wrong, I share a lot of your concerns, but despite everything else it's hard to overlook one thing you mentioned, the seemingly obvious alteration of the disease course by resetting the immune system over the long term if not permenantly. How is that possible if it's not slapping the immune system back in line, and if slapping the immune system back in line has such an effect doesn't that have to mean that the immune system was out of line in the first place?


Your assumption is based on the long held unproved theory that it's the immune system that is initiating the attack on the myelin. But on this very forum we have read comments from several readers that perhaps it's the immune system that is reacting to myelin destruction that comes first and causes the inflammation. Give the patient powerful immune system altering drugs and you are going to shake up that person's entire system and possibly stop the current attack on the myelin.

But how often have we seen the disease continue to march on regardless of these powerful drugs. I believe it is something else causing the real problem and until the researchers are able to identify what this is, all the immune system altering drugs in the world aren't going to solve the mystery. They may offer temporary, short-lived reprieve with the possibility of nasty side-effects but they won't stop the progression of the MS.


There is a lot about the autoimmune theory that I can't shape into a complete picture of MS. In a lot of ways life would be easier for me if there weren't reason to believe that MS is autoimmune but there are just enough smatterings of undeniable proofs which make it too hard NOT to believe it.


That's an interesting comment...if these "undeniable proofs" exist then why hasn't anyone been able to come out and state that MS is an auto-immune disease. Nobody has done that so far and that's all we have is a lot of theory but certainly no proof. The opposite is also true....nobody has been able to prove any other theory as well so what we have today is a disease with no known cause and nothing remotely close to any kind of cure.

I think Finn mentioned earlier that none of us should be too engrained with any certain theories because in the end the truth of the matter is probably going to encompass a mixture of factors which we can't even envision at this point.
Bob


And I certainly agree with Finn on that one....decades of research and still a mixture of ideas, theories and hypothesis...none of which have been proven by anyone!! I guess that's one reason why Dr. Behan labels MS research to date as "abysmal"!!

Harry
User avatar
HarryZ
Family Elder
 
Posts: 2442
Joined: Tue May 25, 2004 3:00 pm
Location: London, ON, Canada

Postby HarryZ » Sat Mar 17, 2007 8:19 am

Ian,

I know Mr Z isn't a big fan of the monoclonal anti-bodies (although no-one complains when they are used to treat cancer),


You've certainly got that one right :D

I thought that I had saved a website link that was an excellent article about monoclonal antibodies that gave me this opinion. Spent 15 minutes trying to find it but without success.

It was a medical article outlining the new "buzz" in drug company research...namely monoclonal antibodies. The writer stated that big pharmaceutical companies were spending millions and millions in this new area of genetically engineered drugs and that they were extremely difficult to work with because of their unpredictability. But despite this, they were pushing ahead at full speed because any slight change to the molecular structure would result in an extended patent protection period.

If you came up with a "winner" monoclonal antibody, the profits would be immense. They have been researched in cancer quite a bit but I'm not too sure at the success rate so far. My concern, however, is using them on MS patients because so little is known about the side effects and possible severe results.

So my distrust in them has to deal with using them on MS patients without doing all the proper safety testing first...and we've already had one problem so far.

Harry
User avatar
HarryZ
Family Elder
 
Posts: 2442
Joined: Tue May 25, 2004 3:00 pm
Location: London, ON, Canada

PreviousNext

Return to General Discussion

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users