Monday, 29 April 2013

Another action for glaterimer acetate


Høglund RA, Holmøy T, Harbo HF, Maghazachi AA. A One Year Follow-Up Study of Natural Killer and Dendritic Cells Activities in Multiple Sclerosis Patients Receiving Glatiramer Acetate (GA).
PLoS One. 2013 Apr 22;8(4):e62237. doi: 10.1371/journal.pone.0062237. Print 2013.

BACKGROUND:Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4(+) Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients.
METHODOLOGY PRINCIPAL FINDINGS: In the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32-48 weeks).
CONCLUSIONS SIGNIFICANCE: Our results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.
Yet another action of glaterimer acetate. It is affect the function of natural killer cells,is this important to the action of glaterimer acetate. These guys natural function is to fight infection and get rid of tumors... Dacluzimab affects NK function but is much more active at limiting relapse rate. What doesn't it do? Not much by the look of it so in another study
 
Sellner J, Koczi W, Harrer A, Oppermann K, Obregon-Castrillo E, Pilz G, Wipfler P, Afazel S, Haschke-Becher E, Trinka E, Kraus J.
Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis.
Clin Exp Immunol. 2013 Apr. doi: 10.1111/cei.12125. [Epub ahead of print]

An altered expression pattern of adhesion molecules (AM) on the surface of immune cells is a premise for their extravasation into the central nervous system (CNS) and the formation of acute brain lesions in multiple sclerosis (MS). We evaluated the impact of glatiramer acetate (GA) on cell-bound and soluble AM in the peripheral blood of patients with relapsing-remitting MS (RRMS). Fifteen patients treated de-novo with GA were studied on four occasions over a period of 12 months. Surface levels of ICAM-1, ICAM-3, LFA-1 and VLA-4 were assessed in T cells (CD3+CD8+, CD3+CD4+), B cells, natural killer (NK) cells, natural killer T cells (NKT) and monocytes by 5-colour flow cytometry. Soluble E-selectin, ICAM-1, ICAM-3, PECAM-1, P-selectin and VCAM-1 were determined with a fluorescent bead-based immunoassay. The pro-migratory pattern in RRMS was verified by comparison with healthy controls and was characterized by an up-regulation of LFA-1 (CD3+CD4+ T cells, B cells), VLA-4 (CD3+CD8+ T cells, NK cells), ICAM-1 (B cells) and ICAM-3 (NK cells). Effects of GA treatment were most pronounced after 6 months and included attenuated levels of LFA-1 (CD3+CD4+) and VLA-4 (CD3+CD4+, CD3+CD8+, NK, NKT, monocytes). Further effects included a lowering of ICAM-1 and ICAM-3 levels in almost all immune cell subsets. Soluble AM levels in RRMS did not differ from healthy controls and remained unaltered after GA treatment. The de-regulated pro-migratory expression profile of cell-bound AM is altered by GA treatment. While this alteration may contribute to the beneficial action of the drug, the prolonged development and unselective changes indicate more secondary immune regulatory phenomena related to these effects.

ICAM= adhesion molecule so is LFA-1 and VLA-4 (integrins) and the selectins some of them go down abit after treatment so they may not bind to antigen presenting cells as well as they could and maybe also may bind less to blood vessels in the brain. What else doesn't GA do?


18 comments:

  1. "So they invented, medicinal compound, most efficacious in every way..............."
    http://www.youtube.com/watch?v=2x8D4T--0v4
    I suspect GA may also solve global warming too ;-)

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  2. I guess if you started taking Copaxone 15 years ago, your chances of transitioning to secondary progressive MS is about 33%. What other drug has shown to be more effective at halting or stabilizing the disease?

    http://msj.sagepub.com/content/16/3/342.full.pdf

    Whats the matter, did Teva pull all of their funding from your institution?

    You guys really don't seem much like scientists.

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    1. Work for Teva by any chance? It isn't going to be around much longer as the new DMTs are much more effective and are likely to be shown to be so when they have been in use for as long as Copaxone has been.
      It's time to move on.
      If you think it's unscientific to not just swallow research findings with no critical analysis, then guilty as charged. However as over the years Copaxone seems to have ticked whatever immunological/neurological box is the flavour of the month despite no convincing explanation as to why this should be for what is after all a random polymer of 4 amino acids, I stand by my opinion.

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  3. No, I don't work for Teva but I was just with RRMS in January. After looking at all of the long term data for the drugs, Copaxone seems to be the most effective and has the least amount of side effects and it won't kill you.

    I guess the point is you have to try to understand what the drugs mechanism of action is instead of just relying on how good a drug is at shutting down the blood brain barrier and assuming this is going to translate into longterm effectivness.

    I'm just glad I can look at the data and come to my own conclusions instead of relying on comments from so called researchers like you who make off the cuff remarks without even following closely to new discoveries about the immune system and keeping up with adanvances.

    By the way, what are your credentials?

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    1. My credentials are that I am a "so called researcher" who has been working in the field of MS for more than 25 years with, if I can be immodest, a modicum of success. I do follow closely the new discoveries about the immune and nervous systems and how they pertain to MS.
      I hope that Copaxone helps you but if not there are now many more alternatives, which there certainly weren't when I started my career.
      Best wishes MD2.

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  4. Most researchers who actually are interested in how the immune system works are becoming aware that the latest data indicates auto-immunity is caused a loss of self-tolerance:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2565852/

    And it appears that Glatemeir Acetate may indeed restore self tolerance as its mechanism of action:

    http://sciencedirect/www.sciencedirect.com/science/article/pii/S0165572809002288

    I guess you can make all of the jokes you want about what is being discovered as to how Copaxone works, but the idea that you can restore self-tolerance by sequestering immune cells, reducing their numbers or preventing them from crossing the blood brain barier as a way to stop MS is really only putting a band-aid on the problem. Sure, it may looks good in a two year double blind study if the key indicator is reduction of MRI activity and relapse rate, but there is not indication that this translates into long term efficacy of reducing progressing which is what people with MS need.

    Having this as your indicator of success only leads to more problems such as is the case with Tsybari and PML(and it looks like it could be problematic with BG-12 also). Hopefully in the near future, other researchers who follow and understand the latest data about what causes MS will come to a true cure.

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    1. Dear Anonymous (5.00 pm) you may be interested to know that we have been working on the re-establishment of tolerance in auto-immune models of MS for the best part of 20 years. In our opinion this will be the best treatment for MS (with the caveat of course that MS really is an autoimmune disease, it may not be) so you are preaching to the (long ago) converted here. However it may only be part of the story and getting it adopted is going to be a huge hurdle.
      http://www.ncbi.nlm.nih.gov/pubmed/15939483
      http://www.ncbi.nlm.nih.gov/pubmed/15927270
      MouseDoctor may wish to comment on how effective Copaxone was in restoring self tolerance in our experimental system?

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    2. "Sure, it may looks good in a two year double blind study if the key indicator is reduction of MRI activity and relapse rate, but there is not indication that this translates into long term efficacy of reducing progressing which is what people with MS need."

      But if you can significantly reduce the relapse rate there is a fair chance you can slow down the time to progression. it's a bit early to tell for the newer DMTs but early indications with alemtuzumab for example suggests that this is indeed the case.

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    3. Auto-immunity is caused a loss of self-tolerance. This is accepted and has always been in my ancient mind a loss of self-tolerance. obvious

      "It appears that Glatemeir Acetate may indeed restore self tolerance as its mechanism of action"

      Whilst I accept that this may be a possibility there is a lot of rhetoric around, it may re-induce tolerance mechanism abound e.g Th2 deviation, T reg formation, T suppressor cell, anergy inducer etc. Perhaps it is just an MHC peptide blocker.

      GA was initially made on the assumption that MBP was a causative antigen. In MS this is not proven, but in some animal strains this is clearly not the case, where antigens such as PLP dominate. Can GA work in these paradims. Yes it can.

      I have seen a lot of action in EAE when GA is added to the immunising emulsion when GA seems to work well if seems to work less well when given subcutanously, as used in humans as to inhibiting relapses after one attack less still,especially not before licensing.

      The pre-clinical data in EAE is not as compelling to my mind or that of MD2, as one may hope. Enough said. This can be leveled at other compounds that work in MS also.

      However, there is evidence that GA offers some benefit to people with MS the trials in MS show this point. The trials also show that it is not as effective as some of the more current new DMT. Therefore whatever mechanism GA may have it is not absolute and there is room for improvement.

      Sorry can't talk about GA experiments.

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    4. On this subject, there has been a discovery in the last few years of what is called a "Tregitope":

      http://www.ncbi.nlm.nih.gov/pubmed/18660382

      It seems within IgG there exist these Tregitopes in the FC region. It is hypothesized that these Tregitopes induce tolerance:

      "When IgG and antigen (either complexed or separately)
      are internalized into the same APC (and TLR ligands or other
      “danger signals” are present), the response to effector epitopes may
      outnumber the Tregitopes, resulting in an initial inflammatory
      response. As antigen is cleared and the ratio of Ig to antigen
      increases, the balance tips toward tolerance, diminishing immune
      response and reducing further tissue damage and adverse systemic
      effects. (Figure 9)."

      This mechanism my be the way IgIV could induce tolerance. Likewise, it is my thought that since antibodies against glatemier acetate are developed this may be the reason why Copaxone induces tolerance:

      http://www.ncbi.nlm.nih.gov/pubmed/21615449

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    5. In the experiment most consistent finding was induction of IgE response 6/6 animals. The IgG responses were less apparent and not consistent. Could IgE lead to skin reactions.

      P.S. Not sure how you get 40% with groups of 6 (Table 2). Not sure what scores mean either they didnt tell us of maybe I missed it ...what were we saying about reporting?

      http://multiple-sclerosis-research.blogspot.co.uk/2013/02/education-arriving-with-consort.html

      http://multiple-sclerosis-research.blogspot.co.uk/2011/12/research-news-reporting-guidelines-for_18.html

      What is evidence that GA or ivIgG really causes immunological tolerance as opposed to transient immunosuppression. Surely you would not need to keep using it if the immune response was effectively skewed and tolerized.maybe you need to keep stimulation.

      Anyway not important thanks for the education on Tregitopes...however so we have yet another mechanism of action for GA.

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    6. There is no definite result that Copaxone or IVIg restores self tolerance but the data is accumulating:

      http://www.ncbi.nlm.nih.gov/m/pubmed/20405183/

      Im not sure why a study was never conducted with IVIg (probably a money issue) but I would prefer a therapy that tries to reinstate self tolerance as opposed to what is comming down the pike.

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    7. I totally agree restoring self-tolerance is what we should be aiming for.

      No glaterimer post just made now you have to remove immunology thinking caps? And explain something else

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  5. Whatever the mode of action, in the UK you currently have the choice of GA or interferon (roughly about as effective as one another as I understand it) for RRMS. There are only more choices for drugs available if you are/become a highly active RR MSer. We don't currently know which of the new breed of drugs will be included in this bracket, if any, so GA or interferon might still be the only valid choice for some. Some of the extension studies do suggest GA is good in the long run, but look at their design and who is included/has dropped out over time.

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    1. Well, if you describe their success rate at the reduction in MRI activity and relapse rate in two years, yes I guess you could say they are about equal. But there is not a shred of evidence that this criteria for "success" translates into long term efficacy of the drug.

      As far as the long term study on Copaxone yes of course people are not going to be able to say on the drug for over 15 years if it is not having any effect (although some people did). Nor would it be possible to have a 15 year placebo controlled double blind study with people of placebo for that period of time. This would be inhumane, but I guess this is what these researchers are expecting as proof of long term efficacy.

      Regardless, even if there were people who dropped out the only way you can really compare the efficacy of the drug is to look at it in comparison to the natural history of MS (the time prior to DMD's) I think the conversion to secondary progressive MS after 15 years is much more than 33% which is what is shown with Copaxone.

      Given the evidence that Copaxone does not start to work for at least six months of continuous use and people naturally do not want to take shots everyday does not mean it is not effective.

      Give me evidence of another drug currently released or on the Horizon that has the track record of Copaxone in the long term.

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    2. Trials show there is some efficacy as to giving you another drug.. the
      only comparison you can have is beta interferon and nutriceuticals

      Until NICE change their licencing arrangements in UK GA and interferons are the only show in town as a first line, unless you have aggressive MS. As for second line therapies, I think you have to fail beta interferons before you have this option.

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  6. You do have to fail interferons first. If you take GA and continue relapsing, you have to switch to interferon first for a year and fail that too (it might work). This is ludicrous as they have a very similar effectiveness. I take GA, and it appears to help me, but I am aware it is mildly effective compared to the new breed of drugs. One of the reasons I chose it was because data suggested it was well tolerated in the longer term...

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  7. I take GA for RRMS here in Canada, I am glad I do not take beta interferons, the side effects would probably kill me :<
    Peter

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