TH17 cells attacking Immature oligodendrocytes

T
Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, Chandrasekharan U, Dicorleto PE, Trapp BD, Ransohoff RM, Li X. Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells.

Nat Neurosci. 2013 Sep 1. doi: 10.1038/nn.3505. [Epub ahead of print]

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κB activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2+ glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2+ glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2+ glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.
Interleukin17 is the principal defining cytokine from Th17 cells. If they remove Act1 which is a signalling molecule of IL-17, but also a signalling molecule of other cytokines, in immature oligodendrocytes then the severity of EAE is reduced. This may suggest these cells are the target for Th17 cells.  Th17 cells have also been found to attach and destroy nerves in other experiments. Studies targeting Th17 cells in MS are ongoing.

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MouseDoctor

8 comments

  • Well then Febrifugine or Halofuginone will be of interest, as both seem to target Th17 and inhibiting IL-17 an leaving the immunsystem intact.

    Also both substances are well researched….but oh no….it seems you can't make a buck out of it…

    https://www.ncbi.nlm.nih.gov/pubmed/22327401

    I wonder if some guy from the reasearch area some day comes up and says: well see we have some potential substance for treating MS but no one wants to invest because there is no money to be made. So take substance xyz. It only costs about EUR abc.yz………ya I am still dreaming 😉

    • Unfortunately there are a load of agents that are reported to affect TH17 cells but you are right if you can't make a buck then no one will do it…I am really sorry to say.

      Who is going to pay for phase II and two phase III and licencing and marketing and and and? No one except pharma. Where are examples of Neuros getting drugs to people with MS that do not have pharma behind them. Sure they can do a trial, but where are the licenced drugs?

      OK

      I will accept any other neurological disease. Come on pharma people out there please enlighten me with a few good examples from the modern era. I would really like to know. I am looking for some good source references

      Just post some weblinks or better still journal titles. Also whilst I am at it can you also give me title of paper where it tells us the cost of developing drugs and also how many drugs fail to get the one to clinic. Its for my review.

      Unless Government change the way that drugs are regulated there is no chance because it is too expensive. Plus there are much better choices than Febrifugine and Halouginone

      If I want to ask the MHRA about how to do regulatory trials for a drug it cost £3-4,000 for a meeting they will tell you they want x y and z and if fact will tell you that you need to do more than any current MS drug has gone through as they are changing the rules. They are funding by the pharma industry and ensure that no one but the pharma industry can do much. If you want to talk to the European regulators it will cost you over £30,000. Thats just to talk. How about holding the regulatory licence at £100,000 plus a year how many nutraceuticals do you need to sell and you have not yet paid any lawyers staff etc etc etc.

      Things do need to change……trust me I know some guy but they are preverbably dead in a ditch not because pharma used a hitman but because they slashed their wrist with the sheer frustration of red tape, inertia against change and lack of support

  • To be candid, the last thing Pharma wants is to cure any disease. Pessimistic …yes but where are the break throughs after all the capital expenditure? The current DMTs are perfect for profits. Pharma tweaks the immune system and counts their $.

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