Boston Cure Editorial: Is inflammation a side-show in multiple sclerosis?

[Guest guest]

http://www.bostoncure.org:8080/article.pl?

sid=04/06/18/1027223 & mode=nocomment

" 1) The initial Campath trial showed that the drug, which kills

specific immune system cells (T and B cells), almost completely

eradicated inflammatory activity and thus relapses. However, it did

not stop clinical deterioration in the volunteers. Initially, it was

thought that disease progression had been arrested in about half of

the small study population, but, as time has elapsed, all but one of

these cases have deteriorated. Similar results have been noted with

ASCT and other forms of immuno-suppression. The authors, Prof

Compston and Coles of Cambridge, UK, concluded that axons were

withering (transecting) due to a loss of trophic support from

oligodendrocytes even in the absence of inflammation. `Trophic

support' describes the process whereby oligodendrocytes feed the

axons substances necessary for their survival. Their first thoughts

were that, by the time secondary progressive MS sets in, so many

oligodendrocytes have been killed that a time-delayed progressive

death of axons was inevitable. They are now experimenting with

introducing Campath at a much earlier stage of the disease, in the

hope that it will arrest the disease before it becomes progressive.

While what they say about delayed axonal transection in response to

oligodendrocyte death seems valid, the timing of their death is not

clear. It seems more straightforward and plausible that they died

after the drug was administered and, crucially, that they died in the

absence of inflammation.

2) Modern MRI technology - DTI etc. - has shown that there are

abnormal signal changes within a significant volume of white matter

in people with MS that appears normal under conventional MRI. These

areas do not correspond with the areas of inflammatory lesions and

might indicate that deterioration is happening in the absence of

inflammatory activity. This work has been carried out by several

prominent MS researchers including the teams of Profs. ,

, Comi & Fillipi. It has long been known that lesion location

shows a very poor correlation with clinical symptoms and perhaps this

explains why.

3) Inflammation has long been known to be a less significant feature

of Primary Progressive MS. In this form of MS, degeneration of axons

progresses largely through some other mechanism. In secondary

progressive and relapsing remitting MS, inflammatory episodes become

less frequent with time but disease progression, or at least

disability, seems to accelerate.

4) Two well-established researchers, Prineas and Barnett have studied

several post-mortem brains of people with MS and noted that

oligodendrocytes are dying before any inflammatory cells have

migrated to the site of the lesion. This would indicate that even

with relapsing-remitting MS, it is not the inflammation that is

killing the oligodendrocytes and is, therefore, not the primary

damage causing mechanism. Inflammation is known to induce temporary

neurological symptoms through nitric oxide blocking and oedema and

may contribute to more lasting damage through axonal transection. On

the other hand, there is some evidence that macrophages may also play

a part in the migration of oligodendrocyte precursor cells to the

damage site and thus in remyelination, so inflammation may be a

double-edged sword.

5) Despite their presence on the market for several years now, it has

not been possible to show that steroids, beta interferons and other

disease modifying treatments have delayed the onset of secondary

progressive MS. This would be very surprising if they really were

having such an effect - one would imagine that statistics would be

able to demonstrate such a delay after as little five years of use.

At some point we must conclude that such drugs are simply reducing

relapse rate (almost certainly by reducing inflammation) and that

this does not convert to a slowing down of the course of the disease

or at least not to a very great extent. Perhaps the huge so-called

trial of MS disease modifying therapies in the UK will be able to

settle this issue.

6) Experimental autoimmune encephalomyelitis (EAE) is an animal model

of Multiple Sclerosis – that is, it is a disease that resembles MS in

several ways. In fact, it is several diseases in several species of

mammal, principally mice and rats. It is brought on by injecting

myelin products into susceptible animals. EAE is almost certainly one

or more autoimmune conditions and researchers have had a lot of

success in treating them. There are hundreds of treatments for EAE

and some of them are extremely effective – in fact, so effective that

one might even call them cures. The problem is that these treatments

rarely convert into successful treatments for multiple sclerosis in

humans. There are only a handful of treatments for MS and none of

these is particularly effective.

None of this evidence denies that inflammation occurs in multiple

sclerosis nor that it does not result in symptoms. However, it does

imply that the adverse symptoms of inflammation may be temporary and

simply a side-show to the key events of oligodendrocyte death and

axonal transection. Inflammation is seen in many neurological

conditions including Parkinson's disease, Alzheimer's disease and

spinal cord injury. Yet, no one suggests that inflammation is the

cause of a broken back nor any of these others.

So where does all this leave us? If inflammation is not the primary

damage causing mechanism, what is? How can so many people be so sure

that MS is an autoimmune disease? Are we relying too heavily on

animal models that describe the wrong disease? Are we spending far

too much research effort chasing after the wrong process? What does

it all mean for the potential new therapies that are close to market -

Antegren, Campath etc? Is relapse reduction a good measure of an MS

therapy?

I don't want to make this all sound too negative. There is clearly a

lot of work that is going in the right direction - oligodendrocyte

precursors, neuroprotection etc. but it is becoming clear that

oligodendrocyte apotosis (programmed cell death) is a significant

feature of MS. Is it principally Fas mediated, C2-ceramide mediated,

semaphorin mediated, caspase mediated or what? If we knew we might be

able to build a drug that interfered with this mechanism and so keep

the oligodendrocytes alive? If we could better describe how they are

dying we might be able to do something about it.

I say all this because it seems to me that too much money and effort

is being spent on the immunology of MS without having shown beyond

doubt that MS is an autoimmune disease. As I read the long list of

research projects sponsored by the NMSS, I see that immunology is by

far the largest category and accounts for 119 out of 311 funded

research projects. I personally believe that there may about to be a

sea change in the science of MS research. As a person with MS, if

it's the right way to go, I certainly hope it happens sooner rather

than later but I'm not optimistic.

Reingold of the NMSS and Henry McFarland of the NIH have both

dismissed Barnett and Prineas' work on the grounds that the disease

modifying therapies work. To dismiss valid experimental data because

it is inconvenient to your fondly held theories is bad science,

although not surprising. The autoimmune theory of multiple sclerosis

is the bedrock of many researchers livelihoods, EAE is not so much a

disease, more of an industry and anti-inflammatory treatments such as

the interferons are multi-million dollar products.

What we have to do is agitate. After all, we are the people who pay

for all these people's livelihoods and the price is our disability. "