Tuesday, 17 December 2013

Stopping Relapses

Pryce G, O'Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165:41-52. 

To date there has been poor translation of immunotherapies from rodent models to treatment of progressive multiple sclerosis (MS). In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T cells followed by intravenous (i.v.) myelin antigen administration, established relapsing disease in EAE can be effectively silenced. However, when treatment was initiated in late stage chronic-relapsing disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression shown by a deterioration in mobility and development of spasticity and indicates that targeting relapsing, immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.

Note this is real therapeutic treatment unlike 99% of other EAE studies and starts after animals have disease. If the same treatment is started after 3-4 attacks then number of subsequent attacks is 0%  and n is greater than 100 but too late and progression occurs. SCH= spinal cord homogenate Ag= antigen d= depleting 

Relapsing EAE can be switched off within 24 hours at any stage of the disease using a combination of transient T cell depletion and antigen-specific tolerance. However, the problem is if there is too much damage, secondary progression kicks in which is no longer responds to the same treatment. The inference is be early and aggressive in treatment and you may stop MS in its tracks. This is an antigen-specific treatment and so does not stop immune response to infections...How is this translated to MS?


  1. A key question is 'how early'? These had only had 3 or 4 attacks and still progressed? Most MSers who seek the very earliest, aggressive treatment are going to be at least a year or two into their disease (post-first symptoms - not necessarily post-diagnosis). You have to be sure you actually have MS, which takes a while and most neuros wont treat CIS with aggressive drugs (I know, I tried) etc... Is there a chance that even 1 or 2 years post first symptoms could be 'too late'? How do we assess this question? Might the early, aggresive approach fail because we're never able to be early enough in reality?

    1. The only way to know is to know is to try it an see,

      The experiment has started with sme people and with more people getting aggressive in the time will be clearer. Next I suspect the aggressive will start at CIS. Maybe Cambridge Neuros will tell us what is their experience with Alemtuzumab

      If there is follow-up of the CISers getting cladribine then we will also see (a) if MS actually occurs and (b) if progression occurs. I suspect because Merck Serono have thrown this drug away this may not happen an the data will not get collected.

      In the beasties (ABH strain) there rarely have more than 4 relapses typically 3 and then there is relapse burn-out. In C57BL/6 there is generally only one attack. We think that even after one attack some tracts will progressively go, however there is plasticity in the system in humans that can deal with the insult.

      Furthermore, in the EAE the attacks are much,much more aggressive than occurs in MS, e.g. in the mice the whole length of spinal cord may be a giant sized lesion.
      Check out post below which brilliantly shows this.
      In the case in the figure after one attack they have lost about 15% of their spinal nerves compared to 0.4%/year shrinkage of brain size in MS and as you can see after one attack they get deficits that never fully recover..0.5 equals a tail with lost movement function but otherwise are running around normally.

  2. The antigen is known for EAE (this is exactly what was used to induce EAE in the first place!), but not in MS. The other article posted today questions the role of myelin as an autoantigen in the initial phases of ms. Do you need to know the antigen in order to induce tolerance?

    1. Yes, we need to know what antigens are involved in MS in order to induce specific tolerance whilst leaving the rest of the immune system intact.
      It is a source of great frustration that definitive antigens in MS have still not been identified.

    2. The work on inducing tolerance by the group in Germany, Switzerland and the U.S. is using 7 common myelin peptides bound to a biodegradable nanoparticle, as posted earlier. From their study it seems this array may be sufficient to induce tolerance. Secondly, how does EBV and Charcot project fit in the auto-reactive T-cell/loss of tolerance theory? As a trigger?

    3. Trouble is that the preliminary results weren't that impressive in the small scale trial with relapses seen in 2 of the 10 patients. They are also not doing a transient T cell depletion stage either in their protocol prior to delivering the antigens, which we have shown to be fundamental for success.
      Maybe things will become clearer in a larger trial.

    4. Is the situation different in NMO? Can tolerance be induced there?

    5. 1. Do you need to know the target,ideally yes,but this will be different between individuals, further more the number of targets broaden with time.

      If you believe the nonsense of co-ordinated determinant/spread which some misguided scientists appear to believe then with only selecting a few peptides you will probably miss the boat. [The study you (Steve S) mention is a safety study it is not clear it definitively worked and the finding that relapses occurred within 10-16 days after administration is a concern]. Fortunately this is nonsense, which anybody bar the dogma machine can show. Determinant spread does indeed occur and this expands with time,but it is not co-ordinated from one epitope to another as the dogma may have you believe.

      At the time of starting these studies we had no idea what the target was except that
      it must be in the spinal cord because this is where the lesions are. So we made a spinal cord mush and the animal selects what is interesting to it. In one strain it will be one bit of a protein epitope in another strain(individual) it may be a different protein or a different bit of the protein. With time we found some of the interesting proteins and the amazing thing here is that if you turn of the response to the dominant pathogenic response, then it can likewise block disease despite the fact that there are other T cell responses to other myelin proteins present. In this case we could do it with a peptide against proteolipid protein. This would breed more hope that the 7 peptide approach (above) could work so maybe it is time to re-think the determinant spread dogma.However if the dominant response in MS is not to myelin basic protein,proteolipid protein or myelin oligodendrocyte glycoprotein but alpha B crystallin, neurofascin, Kir etc,etc. then the myelin peptide approach fails, because the mechanism in my hands and mind is totally antigen-specific and is not by bystander suppression (suppress in the vicinity).For example the proteolipid protein peptide that was successful here, had no effect on EAE induced with myelin oligodendrocyte protein

      However, in MS I think we know what the target cell is, don't we? From there you can get proteins, lipids etc?

    6. 2. In one hypothesis. EBV is a trigger for autoimmunity. EBV infects B cells and this causes the upregulation and presentation of the stress protein alpha B crystallin, which not being expressed in the thymus or the periphery means that humans are not naturally tolerant to the protein. In contrast in most animals alpha B is expressed in the thymus as so they lack alpha B reactive T cells. So now you and most healthy people have alpha B reactive primed T cells rearing to go. No anther virus maybe a HERV becomes activated and stresses the oligodendrocyte to make alpha B crystallin and you have every thing for an autoimmune disease. Interesting in ABH they too lack alpha B in the thymus and when we stimulated these T cells we could get EAE but only in animals having alpha B in their oligodendrocytes maybe because of an infection.

      So the Charcot project aims to limit the viral activation. so that could limit the generation of the target for the autoimmune response, or maybe the autoimmune response is irrelevant and the cells in the CNS are anti-viral and the charcot project will stop this or the Charcot project may fail because MS is autoimmune and has nothing to do with virus after the triggering of MS

    7. 3. NMO what a fantastic idea. You have a target antigen Aquaporin 4 or MOG...what do you think ProfG?, DoctorLove? I feel invigorated...especially after call after yesterdays post and comments.

      In NMO the problem appears to be due to antibody responses. If you do prophylactic tolerance you block T cells and this blocks T cell help for B cells you don't get antibodies.

      But in a primed individual antibodies are there. In terms of the approach however there data is geared to show that it blocks T cell function, if you are from the Th2 brigade this approach could augment antibody responses and remember that intravenous protein delivery is used to boost the antibody response so it could be a problem.

      Experiments are needed

    8. Some time ago I read about a company trying to isolate auto-antigens from each individual patient and use this mix to make an individualized 'vaccine' (was it called Tovaxin? did it became Tcellna?). I did not follow these studies - the approach looked interesting, but very laborious. However, it did not rely on a pre-identified antigen, and it allowed for epitope spreading (either "random" or "systematic"). Judging from the name "Tcellna", they were targeting T cells (I am not sure whether other immune cells were also included in the "vaccine" due to lack of cell separation in the prep). Are these experiments related to your approach in mice? Can it be extended to include depletion prior to "vaccination"?


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