Damping Down Multiple Sclerosis

25 October 2009

Interview with

Professor David Wraith, Bristol University

Helen -   Multiple sclerosis or MS and it's a condition in which nerves in the brain undergo a process known as demyelination.  This is where a layer that surrounds nerve fibres called the myelin sheath which protects nerves and helps them to transmit information becomes damaged.  And this in turn can lead to all sorts of symptoms that include impaired movement, vision, sensation, and cognition.  And the cause of the damage to the myelin is immune system.  For some reason, it fails to tell friend from foe and begins to attack the body's own brain tissue.  This is known as autoimmunity.  But it's been known for 100 years that we can desensitize the immune system by presenting it with tiny doses of the thing that it's overreacting to.  And doctors use this trick today to treat patients with allergies to things like peanuts.  More recently, researchers at Bristol University have found that it can be used to damp down MS and also reduce some of the damage that it does.  Ben Valsler went to meet Professor David Wraith to find out more.

Demylinisation in MSDavid -   What we've realised is that by designing fragments of the target for attack in the autoimmune disease, we can focus our attention on a subset of immune cells called the T cells.  And as such, you can avoid the risks of anaphylaxis or autoimmune disease exacerbation by focusing in on the parts of the antigen that the T cells recognize.  And we have shown that administration of these peptide fragments can lead to desensitization by the allergic and autoimmune state in experimental models that we'd run in the laboratory.  And we recently expanded this or extended this into clinical trials in man.

Ben -   Usually, with a vaccine against the pathogen, something like the flu, you would administer a dead version of the virus and that would present the surface proteins to your immune system and that means you're immune system can be primed to attack these surface proteins when it recognizes them.  So you've been able to isolate the active part of the proteins that only the T cells react to.  And this means that you don't get the overblown immune reaction that could lead to anaphylaxis.

David -   Actually, it'sis more subtle than that because the other thing we've learned is that the immune system is actually a fine balance between what we call effector cells that are designed to battle against the pathogen.  But also, the sort of military policemen who regulate those soldiers that are out there, battling against the pathogens.  And what the military policemen are there to do is really to sort of dampen down and control the immune system.  I mean, when I was talking about this to a BBC reporter some years ago, it was around the time of the first Gulf War and he said to me, "You know, autoimmunity sounds to me just like friendly fire.  It's where the immune system is designed to fight off enemies, but occasionally, things go wrong and it starts attacking its own folks, right?"  And in a way, that's true.  But what we've now learned since then, is that there are other mechanisms designed to dampen down those, sort of, pathogen clearing T cells.  And if you look in parasitic infections, the cells we are designing our vaccines, are peptides, to induce are in fact present there and are preventing the immune system over-attacking the response to the parasite.  And this is why one of the mechanisms that has allowed parasites to evolve, to live along with man.

Ben -   So whereabout are you in the trial so far?

David -   We just conducted a small phase one strike two clinical trial and the MS MRIregulatory authorities asked us to conduct this in patients suffering from quite severe MS already.  So one wasn't expecting any dramatic change in the condition with these individuals.  Really, when you do a safety trial, you're primarily trying to prove that the approach you are taking and the treatment is safe and well-tolerated.  And indeed, this was the case.  There was one individual in the trial who was suffering from severe loss of visual acuity and almost was clinically blind in one eye.  And through the course of the treatment, her vision was clearly recovered and this is very, very encouraging.  Obviously, one has to do much more extensive trials to prove that this is a more general phenomenon.  And of course, knowing what we know about multiple sclerosis, I think everybody would accept that this is just the type disease why you need to start treating as early as possible.  So our next trial will be a much more extensive trial in patients with an earlier stage of disease.

Ben -   Increasingly, with medicine, we're looking at treatments for an individual, knowing that everybody is genetically unique.  Genes we know code for proteins and it's parts of proteins that you're hoping to encourage the immune system with.  So, could it possibly be that everybody will respond differently and this may be an enormous task of finding exactly which bits of which genes code for which bits for which proteins in order to successfully make a vaccine?

David -   Well, I think that's one of the points about autoimmune diseases that we really do understand.  There's a genetic contribution to these diseases.  But actually, of that, the major genetic contribution or predisposition to disease comes from a set of genes called the human HLA genes or the histocompatibility complex genes.  And these are the genes that code for proteins that are the receptors for the fragments that we're talking about.  So in fact, whereas something around 25% of the population express a particular HLA molecule that we're targeting, around 70% of MS patients carry that receptor.  So indeed, our vaccine, if you wish to call it that, would be expected to be effective in about 70% of the MS sufferers in the UK at least.  But in fact, there is a good deal of cross-binding or cross-reactivity between the particular HLA molecules that we are targeting.  So one way to expect it to be effective in over 90% of people.

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