Tuesday, 21 February 2012

Education: How does Fingolimod (Gilenya) work.

You (Matt) Wrote : It seems like stopping white blood cells from entering the blood would be very very dangerous..... I don't understand how people on Gilenya don't just get sick....."


The blood flows round the body to deliver nutrients to the cells of the body. Fluid (plasma) can leave the body from capillaries (smallest blood vessel between an artery (vessel comming from the heart) and a vein (blood vessel going to the heart). This fluid (now called lymph) bathes the cells and drain into lymph glands via lymphatic vessels. Some white blood cells (dendritic cells) move from skin to lymph glands via these lymphatics and a current idea is that these cells transport information to the lymph glands that there is a infection to deal with. In the brain the dogma is that there is no lymphatic drainage, others suggest there is some limited drainage to the cervical lymph gland. In the lymph gland these dendritic cells and the lymph encounter lymphocytes (white blood cells T and B cells)
White blood cells circulate round the blood and can enter lymph glands via specilalised blood vessels called high endothelial venules (small vein) blood vessels using a molecule called CD62L which binds to a sugar molecule on the high endothelial cells.


The NAIVE cells made in the bone marrow and moved via the blood and then into lymph glands. There they encounter lymph and dendritic cells and if they are NAIVE lymphocytes cells (that have never seen their target before) they multiply when dendritic and macrophages show the naive lymphocytes their intended target (e.g. virus, bacteria or in case of autoimmunity- a protein or lipid derived from the body). So where you had one cell you know have lots. These cells also change their coat (differentiate) and put up markers (such as CD44 and CD49d = protein that tysabri blocks) that allow these cells called EFFECTOR cells to enter tissues to seek out and destroy the infection. These cells may sometimes down regulate CD62L so they do not go back into lymph nodes (EFFECTOR MEMORY CELLS). Other cells become MEMORY cells so that when they see the target (e.g infection) again the they respond quicker and more vigourously to produce effector cells. Some of these memory cells (CENTRAL MEMORY CELLS) travel through the lymph glands. The white blood cells then exit the lymph gland, possibly traveling to the next lymph gland via the Efferent lymphatics (lymph vessel that leaves the lymph gland). This eventually drains back into the blood and from there the white blood cells circulate round the body.


In cases of MS the thought is that these white blood cells then enter the brain and thinking that oligodendrocytes and myelin are infections they cause damage that leads to demyelination and symptoms of MS. Now Gilenya works by blocking the action of a molecule (Sphinosine-1-phosphate receptor) that is a gatekeeper of the efferent lymphatics that stops the white blood cells exiting the lymph gland.


However only the naive and central memory populations, which are thought to be involved in MS, use this molecule to exit the lymph cells, whereas effector memory cells that fight infection do not. Therefore whilst Gilenya is a potent immunosuppressive and can inhibit relapsing disease the hope is that it does not stop one from fighting off infections.
Another way to think of this is to imagine a racing track (blood system) and the pitstop (lymph gland) and the racing cars (white blood cell). Cars have to go into the pitstop to change their tyres and then off they go back to the blood. The team managers can call in the cars by perhaps putting out a flag so the cars come in. The naive (yellow) and central memory (green) cars run on Goodyear tyres whereas the red car (effector memeory) cars run on Pirelli tyres. Now gilenya blocks the Goodyear truck from delivering tryes and so when the cars come into the pits for a tyre change there are no spare tyres and so the yellow and red cars get stuck in the pitstop and have to retire from the race. However, the red car can just keep going and protect against infection.


For those of you interested, below is a video infomercial for Doctors made by Novaritis, which indicates how fingolimod may works. The first half talks about what we have said above.





CoI:None

16 comments:

  1. I am going to have to spend the next few days researching this. There are a lot of basics I didn't understand.

    1. I didn't realize lymph nodes were all over the body.

    2. I hadn't heard the terms gliosis or astrogliosis before even though it sounds like they play a huge part in MS. My initial idea is that lesions are areas of gliosis bit that's after a sixty second Wikipedia review.

    3. I had not exactly understood the theory that oligodendricytes were being destroyed in MS, although I was aware that oligodendricytes either produced or helped produce myelin.

    4. The video says essentially "don't worry about clogging the lymph nodes, they're always full of lymphocytes" but it's awfully suspicious that there are heart issues and the lymph nodes are clearly more full than usual.

    5. I had not committed to memory that lymphocytes included exactly t, b, and natural killer cells.

    I could go on and on but won't. I just wanted to make sure to express my appreciation.

    Anyway, this post is a like a crossword puzzle with 100 sub-challenges to solve. I look forward to the challenge. Thank goodness for Wikipedia. Take it one term at a time a next thing you know I start understanding.

    ReplyDelete
  2. If you think of gliosis as a scar.
    Gliosis is activation and division of astrocyte, think of it as a scar.

    This is where multiple sclerosis comes from it means multiple scars.

    ReplyDelete
  3. Have a hunt through the blog, there are links to many bits of the puzzle
    and also youtube there are some good teaching videos if you have the time.

    We will post more educational stuff in due course

    ReplyDelete
  4. Vidoes on youtube by Khanacademy are good

    http://www.youtube.com/watch?v=FXSuEIMrPQk

    ReplyDelete
  5. check out Lesion formation on blog

    http://multiple-sclerosis-research.blogspot.com/2011/12/education-espresso-pathology-lesion.html

    ReplyDelete
  6. Hey Becky,

    It's interesting that you start off saying you have nothing to sell and end suggesting people buy a book.

    We live in a wonderful age where credible online resources are available to refute your fraud.

    http://www.snopes.com/medical/toxins/aspartame.asp

    http://en.wikipedia.org/wiki/Aspartame_controversy

    "The methanol produced by the metabolism of aspartame is absorbed and quickly converted into formaldehyde and then completely converted to formic acid, which, due to its long half life, is considered the primary mechanism of toxicity in methanol poisoning. The methanol from aspartame is unlikely to be a safety concern for several reasons. The amount of methanol in aspartame is less than that found in fruit juices and citrus fruits, and there are other dietary sources for methanol such as fermented beverages. Therefore, the amount of methanol produced from aspartame is likely to be less than that from natural sources. With regards to formaldehyde, it is rapidly converted in the body, and the amounts of formaldehyde from the metabolism of aspartame is trivial when compared to the amounts produced routinely by the human body and from other foods and drugs. At the highest expected human doses of consumption of aspartame, there is no increased blood levels of methanol or formic acid,[8] and ingesting aspartame at the 90th percentile of intake would produce 25 times less methanol than would be considered toxic."

    ReplyDelete
  7. Becky Miller said...

    I just finished editing and illustrating a book for a well-known food scientist, Woodrow Monte, PhD, in which he reveals in detail his discovery of the cause of Multiple Sclerosis. MS is on the rise, and avoiding it - and in some cases even curing it - is actually very simple. This is not conspiracy theory or snake oil; Dr. Monte is not selling any products. He is a good man and excellent scientist who has devoted his life to helping people. His work is sound and his conclusions are undeniable in face of the evidence. Dr. Monte has been working with several MS patients who, based on his findings, are getting their lives back. One who was in very bad shape not long ago is now driving and riding her horse for the first time in six years.

    The simple one and only cause of MS is exposure to methanol. It is the methanol in cigarettes that is responsible for the known link between MS and smoking. It is the methanol in Ditto machines that is responsible for the epidemic of MS in school teachers. And it is the methanol in aspartame, which is heavily consumed in diet sodas, that is responsible for the explosion of MS in the past 30 years since its approval by the FDA for use in diet sodas. Methanol is found in lesser amounts in several common foods as well, but all are easily avoided. When consumed, it is converted by the enzyme known as Alcohol Dehydrogenase Class 1 (ADH1) into formaldehyde inside the body’s most sensitive tissues. Once inside the brain, the formaldehyde quickly attaches to the myelin sheaths, and that change prompts the body's white blood cells to devour the damaged sheaths. The myelin sheath can regenerate if it is not yet entirely destroyed - which is why MS sufferers experience periods of remission and why avoiding methanol in the diet and environment can cure MS if it hasn't gone too far.

    THEN CAME THE PLUG AND WEBLINK THAT I HAVE DELETED.

    IF YOU WANT TO READ ABOUT DR. MONTE YOU CAN DO YOUR OWN HOMEWORK WITHOUT BEING SOLD A BOOK VIA THE BLOG.

    ReplyDelete
  8. Please read Matts response above this post

    ReplyDelete
  9. Re: "The methanol hypothesis"

    Unfortunately, this is nothing else but a hypothesis. The evidence is very flimsy and the science against this being a factor very strong. Again I refer you Bradford-Hill and the science of causation.

    ReplyDelete
  10. Becky Miller
    If this theory was correct, why are relapses stopped when lymphocyte entry into the brain is blocked?
    I'd be fascinated to know.
    The theory sounds like quackery to me.

    ReplyDelete
  11. While Science Sleeps, by Woodrow C. Monte PHD, Emeritus Professor of Nutrition and Food Science, Arizona State University.

    Available from all good book pulpers around the globe.

    ReplyDelete
  12. Prof G and mouse doctor,

    rmforall and Becky Miller are "comment bombing" your site. It's highly likely that they are the same person.

    They are copy and pasting pre-written comments that are designed to be too long and complex for anyone to respond to. The goal is not a response but to advertise a product.

    You should feel free to delete all current and future comments from rmforall and Becky Miller because they are trying to take advantage of your site and MS patients. They do not mean well. They will most likely come back under different pseudonyms but their patterns will be the same and will get easily recognizable.

    These comments will actually stop productive discussion on the site. They don't care. Feel free to delete this comment as well. They will of course accuse you of censorship, but don't worry about it. They are hoping your fear of being a "censor" will help them sell products.

    They will throw endless questions at you in the hopes of getting you continually discuss their product. Only solution is to delete all comments from them, respond to none.

    ReplyDelete
  13. Dear Matt
    Thanks for the head up.

    We regularly delete any comments with links attached.

    With regard to endless questions they will waste their time as we will not answer. G stopped ages ago.

    They will annoy people recieving email alerts more than us.

    ReplyDelete
  14. An exhaustive analysis of the medical and scientific literature,
    authored by a uniquely qualified food scientist, persuasively reveals
    the cause of MS and describes a path to recovery and prevention.

    The symptoms of Multiple Sclerosis are identical to those of an
    uncommon form of poisoning -- methanol poisoning.
    Individuals who have been exposed to this poison over a long period of
    time, in fact, develop MS.
    This poison -- methanol -- is a major component of cigarette smoke,
    which, until now, has been the only known cause of Multiple Sclerosis.

    Dr. Monte's compelling work reveals that this poison is also contained
    in certain foods that are canned and smoked or have had the insidious
    sweetener, aspartame, added to them.
    Unfortunately, the truth has been obscured due to the fact that
    methanol is a poison only to humans and not to (laboratory) animals....

    ReplyDelete
  15. The above from rmforral with link removed

    ReplyDelete
  16. Matt I usually repost the comment with link removed so we do not censor but we try not to advertise....for others.

    ReplyDelete

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