Research: Another action for Gilenya

Alterations in sphingolipid metabolism are described to contribute to
various neurological disorders. We here determined the expression of
enzymes involved in the sphingomyelin cycle and their products in
postmortem brain tissue of multiple sclerosis
(MS) patients. In parallel, we investigated the effect of the
sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin
metabolism in reactive astrocytes and determined its functional
consequences for the process of neuro-inflammation. Our results
demonstrate that in active MS lesions, marked by large number of
infiltrated immune cells, an altered expression of enzymes involved in
the sphingomyelin cycle favors enhanced ceramide production. We
identified reactive astrocytes as the primary cellular source of
enhanced ceramide production in MS brain samples. Astrocytes isolated
from MS lesions expressed enhanced mRNA levels of the ceramide-producing
enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from
control white matter. In addition, TNF-α treatment induced ASM mRNA and
ceramide levels in astrocytes isolated from control white matter.
Incubation of astrocytes with Fingolimod prior to TNF-α treatment
reduced ceramide production and mRNA expression of ASM to control levels
in astrocytes. Importantly, supernatants derived from reactive
astrocytes treated with Fingolimod significantly reduced
transendothelial monocyte migration. Overall, the present study
demonstrates that reactive astrocytes represent a possible additional
cellular target for Fingolimod in MS by directly reducing the production
of pro-inflammatory lipids and limiting subsequent transendothelial
leukocyte migration.

The blood brain barrier keeps stuff out of the brain to maintianin its health, it consists of speciallised blood vessel cells that bind together tightly to make them inpenetrable. This is facilitated by factors produced by astrocytes that contact the blood vessel. This group finds that Gilenya may act on astrocytes to increase the production of a molecule that helps make the blood brain barrier less leaky to monocytes, which are macrophages in the blood. This suggests that Gilenya may not only stop (lymphocytes) white blood cells from entering the blood during MS but may also interfer with white blood cell (monocyte) entry into the brain also so a double whammy of benefit.

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  • Mouse Doctor,

    I am due to start Gilenya as soon as RLH get the nod. I read your blog, but I found that due to my Limited intelligence levels I was unable to understand what you are telling me.

    Please, explain that again, like I am a 12 year old!



  • Sorry there were a few mistakes in the original post.

    Gilenya works because it stops white blood cells getting into the brain where they trigger relapse. This is because the white blood cells are trapped in the lypmph glands so they can not get into the blood so they do not get in the brain.

    This new study also suggests that gilenya can also act on cells in the brain so that they make the the blood vessel less permeable to stop white blood cell migration from the blood to the brain.

    Therefore there is a double whammy to stop cells getting into the brain.

    This also indicates that the drug will affect lymphocyte white blood cells and monocyte white blood cell types again a double whammy aimed at blocking a damaging immune response

  • "Gilenya works because it stops white blood cells getting into the brain where they trigger relapse."

    Sorry MD, but this is just a conjecture. If this was true, then MS would be a proven autoimmune disease, which is not.

  • VV
    Strange then that Gilenya actually significantly reduces relapses in MS patients, indicating in the very least that there is an autoimmune component. Now please go away and commune with your CCSVI "believers"!

  • MD2, it has never been shown that there are white blood cells in MS lesions PRIOR to any dead oligodendrocyte around. On the contrary, the opposite has been documented. So, it is more possible that there is a normal immune reaction than any autoimmune component.

    You seem to know what a relapse exactly is. Strange, since Prof Gavin Giovannoni has told us that "relapse" is a well overloaded notion that gets different meaning from trial to trial and that the current consensus is liable to change at any time. Apart from that, Gilenya downregulates a normal immune behavior, that is the free white cell circulation. If this has some effect, it only proves that there is some kind of damage to which the immune system just responds. It does not prove that this response is abnormal.

    • actually you are wrong. I am a basic scientist that has looked at many MS lesions, including ones from people who died from their first attack. White blood cells are there my friend. You can see the white blood cells devouring the myelin…. sorry to burst your bubble. This is why every therapy so far has been immunological

    • also, t-cells need not be present at the time of a lesion to induce a response. they just pull the alarm so to speak.

  • VV
    Whatever. No matter what I or anybody else says will convince you so I'm not going to bother.
    The Prines studies (in a minority of cases) which may be atypical presuppose that these oligodendrocyte lesions may go onto become inflammatory after oligodendrocyte apoptosis. That may not be the case.
    If this was the sole driver of MS, why does radical immunosuppression by something like CAMPATH 1 completely stop the disease and indeed reverse progression in some cases. That couldn't happen if MS was caused by oligodendrocyte loss alone independent of inflammation.

    Anyway, I'll waste no more time on you.

  • There is a constant mix up of terminology. When you say "autoimmune" i presume that you mean an unprovoked reaction of the immune system (without injury of any kind), while "inflammation" is the result of ANY immune response, be it provoked or unprovoked.

    When i remind you that there is currently no proof that MS relapses are the result of unprovoked immune responses, you slip your argument to the presumed bad effects of inflammation. If you didn't avoid discussing to the point maybe we could sort something out for the benefit of your readers.

    As for Campath: So far it has been tested versus INF-b, but not versus placebo. If we take into account that the long term benefit of INF-b treatment is at least unclear, then the existing Campath trials can't provide something useful. But let's check them, nonetheless.

    The CARE-MS I involved early diagnosed MS patients with no previous medication other than steroids. After 2 years, no benefit could be seen regarding disease progression:
    "Statistical significance was not achieved for the second primary endpoint, time to six month sustained accumulation of disability, as compared to Rebif"

    What about the infamous 5 year follow-up study?

    This study used only 198 of the initial 334 patients of the CAMMS223 study. Which of them where they? Probably those who did better in the first place, in other words, those with milder MS. This study is the kingdom of all biases: no placebo group, selected patients, funded by the manufacturer. Why pay any attention to its results?

    Regarding the 17hour lesion: You repeat that this may not be the case with all MS lesions but you fail to bring a SINGLE case to support it. Until somebody finds just one lesion full of white blood cells and without injury of any kind, EVERYBODY is forced to assume that all lesions develop like the Prineas lesion.

    You say that inflammation is bad because suppressing it reduces relapses. You know that relapses of early RRMS usually leave no trace on disability and get resolved almost completely. So there is really no way to tell whether relapse reduction has any benefit in the short run. Besides this, don't you find it strange that most relapses eventually resolve and rarely go out of hand to cause substantial damage? Isn't this evidence that they are well handled by fine-tuned immune systems?

    All puzzles regarding relapses and drug effects become clearer if you consider relapses as a kind of "pain". By reducing pain you don't reduce the injury. You may get a better feeling in the early stages, but eventually the accumulation of injuries will come at you.

  • You know that relapses of early RRMS usually leave no trace on disability and get resolved almost completely.

    "I would suggest that there are people that have relapses that do indeed have disability"

  • Autoimmune is what it says a self directed immune response. This typically involves the adaptive immune response which often recruits the innate immune system

    Inflammation is a protect and repair mechanism that is designed to destroy invading pathogens and then repair the damage caused.

    This can involve the adaptive and innate systems

    Inflammation is part of the autoimmune response.

    Inflammation does not need to be autoimmune.

    Provoked verses unproked This is all your words in your concepts not mine…..

    what if what if…

  • In order to call a response "autoimmune" you have to make sure in advance that there is no pathogen or injury involved. Are you sure there is nothing wrong in human CNS prior to the adaptive or innate immune response?

  • In order to call a response "autoimmune" you have to make sure in advance that there is no pathogen or injury involved

    Nonsense…I am afraid there are post-infectious autoimmune conditions

  • Furthermore there does not need to be a T cell in sight so you need to accomodate this in your worldview

  • So, since the immune system of MSers is messed up and needs "fixing" by a greater force, how come and it doesn't cause any serious damage elsewhere in the body?

  • Dear VV
    I suggest you read any immunology text book and you will understand why I need not waste my time responding.

    specificity is a beautiful thing

  • "specificity is a beautiful thing"

    Like the specificity of MBP. For years it was the primary candidate of the MS autoantigen, although abundant in the peripheral nervous system also. The lack of specificity didn't matter back then. Now, no one seriously talks about T-cells attacking CNS myelin. At least, Prof Prineas doesn't.

    • I know professor Prineus, so I wouldn't go around quoting him. He is a promotor of oligodendropathy (that may or may not be immune incidentally). A wonderful theory but not one that necessarily contradicts an immune cause of ongoing tissue damage.

      Also, there are indeed people with MBP responses. There are hundreds of potential targets in Myelin of which MBP is just one. Myelin is an incredibly antigenic, phosphorylated lipid raft. It would make sense that it isn't just one pathogen. That's what is meant by specificity. It is people like you that cause many people to refuse life altering immunomodulating therapies.

  • Exactly MBP was always a rubbish potential autoantigen…I agree with you for once.

    However T cells never directly attack myelin as it does not express MHC, so again get on reading that text book and it all becomes clear.

    No-one talks…..You are going to the wrong meetings and reading differnt papers

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