Halfway to a Cure?-Published

#MSResearch #MSBlog Both parts of a potential cure are safe, just need to put them together. The effect without the side effect

The problem with all current MS treatments is that they are not very effective and have side -effects or they are more effective but have more serious side-effects, This is because these treatments remove part of the immune repertoire that is used to fight infections and cancers. The only thing that gives the immune response its specificity is the target recognition receptors on white blood cells. So if you could only target the immune response that is causing the disease and leave the rest of the immune system intact you would have a treatment that works but would have essentially no side effects…….. The Holy grail of Treatments in Immunology.

Lutterotti A, Yousef S, Sputtek A, Stürner KH, Stellmann JP, Breiden P, Reinhardt S, Schulze C, Bester M, Heesen C, Schippling S, Miller SD, Sospedra M, Martin R.Antigen-specific tolerance by autologous myelin Peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med. 2013 Jun 5;5(188):188ra75. doi: 10.1126/scitranslmed.3006168.

Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1–20, MOG35–55, MBP13–32, MBP83–99, MBP111–129, MBP146–170, and PLP139–154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 10 9 = 1 US billion cells) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.

We have talked about this exciting approach before when it was presented in abstract form at ECTRIMS. So rather than write again follow the link and read. http://multiple-sclerosis-research.blogspot.co.uk/2012/10/ectrims-half-way-to-cure-of-autoimmunity.html 

This shows you need to give a lot of antigen it may be easier to make biodegradable beads and the peptide mix so you do not have to individualise the approach as the cells are just dead carriers to keep the peptides hanging around.. 

Much easier than have bone marrow transplants. Will it work well the mechanism states that T cell proliferative responses (reversable with IL2) with be reduced

This concept was borne in the Dr Windy Miller Lab or is that Chicago Steve and is truly a translational approach from mouse to Man so well done to Steve Miller and the Clinical Crew who got this off the ground.

We (Team G) believe that they should deplete the T repertoire before delivering the the intravenous myelin antigens. This should be done when the immune cells are recovering from the depletion and it causes a re-education of the immune cells such that they are no longer self aggressive. 

Depletion of immune cells in MS has already been done and this approach is safe so if you put this current approach with the deletion event you can make the two approaches, which may be not optimally effective when used individually and may completely stops relapsing disease when used in combination. 

P.S. We may have had our bit to play in this one…..according to our Spies but that’s another story.

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    • This is a particular problem with Campath, but has not been so common with other immune-depleting drugs. This suggests there is a solution to the secondary autoimmunity!

      I know Prof G has an idea or three on this..and suspect they could work…but what's new about him having an idea or three…that's why he is Prof G.

      In animals the depletion only needed to be for a week or so, but for some of the human depleting drugs the depleting effect is for about 2-5 years. However, you need the immune cells for the immune tolerance to work. There is a challenge to the translation

  • Are antibodies against these antigens developed? It seems that if you have an significan excess of auto-antibodies produced against a self antigen, tolerance may be induced. At least this is the theory with "Tregitopes" and a proposal as to why IVig may induce tolerance. So it may be possilbe that this is the mechanism of action behind this approach.

  • There may or may not be antibdoies against these antigens but this approach is about controlling T cell function not antibody function.

    As to the mechanisms of action and "Tregitopes" I doubt this has anything to do with the mechanism. This approach causes T cell anergy (Cell present but functionaly silenced) as a major mechanism, and central (in thymus) and in some cases a peripheral T cell deletion via the weedkiller effect (Stimulated to death) and also induces IL-10 producing regulatory cells, the Milller Lab would add Treg and TH-2 and CD8 T suppressor cells as the tolerance mechanism has changed with the Fad of the minute

    The mechanism of action is quick so it has no time to form new antibodies if they are not there already. Could antibodies be produced…maybe the i.v. route is an antibody boosting route… and could also be the case if it

  • Interesting that there were disease exacerbations in some of the treated MSers (mysteriously this information is missing from the press releases) so looks like the limited pool of myelin peptides used in the study isn't big enough?
    Of course they have also opted not to go with initial T cell depletion before treating with the antigen-coupled cells which again in my view is a mistake.
    Still think our report of 2005 that you can do this with antigen coupled beads is the way to go.

  • The "C" word rears its ugly head. Every post with cure induces a cringe. That said, induction of tolerance addresses the autoimmune response. But what if MS is a degenerative disease with an autoimmune component? Halfway to a cure is appropriate. Onward.

    • the murderous rabbit…. the knights get an outing this week
      wondering if we will lose a few:-)

    • Maybe the nanosphere with common peptides will induce tolerance and silence inflammatory response…………….the "holy hand-grenade of Antioch" 🙂

    • "One or both are wrong" is so confusing!

      Should we pin our hopes on any one turning out to be correct?

      What is Prof G's opinion on this?

    • Prof G will pin hopes on the EBV theory but if the Miller myelin peptide theory were correct then the two are not the same although one could construct a theory where EBV infected B cells present myelin antigens that cause the problem. Now put the DrCryAb therory in the mix and you get EBV infection of B cells that cause autoimmunity to a none myelin antigen.

      You know which is correct when a treatment targeting a hypothesis turns out to work. That is why many avenues are being taken at the same time, why put eggs in one basket.

  • is all this fighting
    helping I don't think so Im not happy with the ms is autoimmue theory why should we get worse ive already lost car,drivers licence walking, high heel shoes!,husband,trying to keep my kids away, money, house I just want a reprieve



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