Research: GM-CSF a Target for T cells


Although the role of the T(H)1 and T(H)17 subsets of helper T cells as disease mediators in autoimmune neuroinflammation remains a subject of some debate, none of their signature cytokines are essential for disease development. Here we report that interleukin 23 (IL-23) and the transcriptionfactor RORγt drove expression of the cytokine GM-CSF in helper T cells, whereas IL-12, interferon-γ (IFN-γ) and IL-27 acted as negative regulators (block production of GM-CSF). Autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A or IFN-γ, whereas GM-CSF secretion by interferon gamma(-/-), Interleukin17a(-/-) helper T cells was sufficient to induce experimental autoimmune encephalomyelitis (EAE). During the disease effector phase, GM-CSF sustained neuroinflammation via myeloid cells that infiltrated the central nervous system. Thus, in contrast to all other known helper T cell-derived cytokines, GM-CSF serves a non redundant function in the initiation of autoimmune inflammation regardless of helper T cell polarization.

Many people think that autoimmune disease and T cells are central to the development of autoimmunity. The fundementalists immunologists gave us the Th1 and Th2 paradigmn based on the idea that interleukin 12 made gamma interferon-secreting Th1 cells. So the mantra was block IL-12. However the reagent they used to do this also blocked IL-23 and when they found out that IL-12 was not important for the development of autoimmunity in mice, but IL-23 then Th1 cells had to be superceded. IL-23 is involved in the development of IL-17 secreting cells and Th17 cells were born and the route of all evil in autoimmunity. So block IL-17 was and is the new mantra.

Only problem is when you actually look at the mouse data in the majority of papers this approach actually does not do much despite what is written in the results, you only get a minor delay and small reduction in neurological signs, so dogma is maintained. Cells that transfer the disease do produce IL-17 but they may then can stop this and secrete interferon gamma. So now you have Th17-induced EAE and Th1-induced EAE, so double groan as some people now feel that you need to do both models to prove a point.

However, the IL-12 bandwagon started pharma off and so they made anti-IL12 antibodies and tried them in MS and they failed,  but they were so good in EAE. But were they?. Well when they were given before disease had even started they were ace and wiped out disease. However if given to try and stop the second attack they were pretty useless, which was ignored by the dogma machine and you do not treat MS before you know you have least not yet.

So this failed in mice and humans and because they used an antibody that inhibited the common chain of IL-12 and IL-23…IL-23 may be off the agenda.

Now there may be some data that shows blocking IL-17 is rather rubbish as stopping mice from developing disease, it may be much better at inhibiting relapsing disease and when Th17 cells were tracked they were damaging nerves rather than initiating the initial attack, so there may be something in the Th17 story.

A trial has recently completed looking at inhibiting IL-17 in RRMSers and these people are been watched in a follow up study …..we shall see but there have been mutterings of promising results in other immune diseases.

Now the study above that was reported last year that you have asked about could have, but did not yet make a new dogma (probably because it was not born in the USA, where most -immunological-dogmas originate) and we would have had the ThGMCSF of Thcsf2 cells. GM-CSF is sometimes
used to stimulate the production/mobilize stem cells before you bone
marrow transplants and so blocking GM-CSF may have its complications,
but that is the case for any treatment. This study would suggest that blocking GM-CSF could be beneficial in RRMS.

This study indicates that cells that produce granulocyte macrophage colony stimulating factor= CSF2 are the bad boys and this is the key cytokine that drives cells to cause EAE. You don’t need IL-17 or gamma interferon to do this. IL-23 stimulated this and IL-12 blocked the development of cells making GM-SCF. They blocked GM-CSF and EAE was inhibited (although some of the effects were reported were a bit of a Shania, some looked good) so we have a new treatment option.  I wonder if  the anti-GM-CSF is actually affecting the macrophage/microglia?

However, before we can say “Clinical Trial” you already have one.

There is clinical trial with an inhibitor of GM-CSF called MOR103 that is currently recruiting in Poland, Germany and UK, if interested press the link for details

CoI: None 
I have no links with the company running the trial. 
Maybe Prof G knows more about it.

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  • Prof G – how does this fit into an EBV view of MS?

    I read the other day the following, too: "Warren and Catz, (1994) studied the relative frequency of auto- antibodies in optic neuritis and multiple sclerosis CSF and their findings suggested two immunologically different forms of multiple sclerosis: a common form with autoantibodies directed against MBP (myelin basic protein) and a less common form associated with anti-PLP (proteolipid protein) antibodies. From the descriptions of the five patients with anti-PLP antibodies, it is likely that three of them had primary progressive multiple sclerosis. Remarkably, none of the three patients had signs of intrathecal IgG-synthesis and all were oligoclonal band negative. Differences between relapsing/ remitting and primary progressive multiple sclerosis in the frequency of other autoantibodies, notably anti ganglioside antibodies, have also been reported (Acarin et al., 1996)"

    All of these different variants of MS – does this suggest a different virus affecting each person with a different variation? Or just a different immunological response to the same virus?

  • This is interesting as well:

    "An EBV lytic transactivator, Zta, induces an immunosuppressive cytokine interleukin 10 (IL-10) in B cells….(and) the IL-10-inducing effect involved at least two immunomodulators that were upregulated by Zta and secreted from NPC cells: granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostaglandin E2 (PGE2). Zta was recruited to and activated the GM-CSF promoter, thus upregulating GM-CSF expression."

    So – if EBV infection causes a cascade that initiates Zta, that induces IL-10 and that then upregulates GM-CSF… downregulating GM-CSF might have some impact. But it seems to be targeting a consequence rather than a cause…. no?

  • One final thing – this area of GM-CSF really interests me you can tell – I think that this is interesting.

    GM-CSF is, reportedly, required for the immune attack in MS, at least in mouse models.

    It seems that autoreactive helper T cells specifically lacking GM-CSF failed to initiate neuroinflammation despite expression of IL-17A.

    So…. how to downregulate GM-CSF?

    Well you can go on a clinical trial and get injected.

    It seems that they may have tried this before with a drug called Sirolimus (Rapamycin).

    Rapamycin was shown to inhibit GM-CSF induced neutrophil migration…

    but nothing came of the clinic trial so one assumes it didn't have the effect hoped for.

    But if you believe that there is something still in this…. perhaps you can help to downregulate GM-CSF naturally???

    This work into Luteolin showed that it suppressed the expression of GM-CSF

    And guess what… Luteolin….has been looked at as a therapeutic option for MS…

    And guess where Luteolin can be found?


    With some big results: “This was just about as potent an inhibition as anything we had seen previously,” the lead on that research said.

    Perhaps we need to eat more of the stuff.

    What do you think Prof? Mouse Doc?

    Celery shakes for breakfast?

    Iain O


    This a post about the paper mentioned in this post. So read it an you can have a different take on the same story.

    "How do you inhibit GM-CSF it has been done before with a drug called Sirolimus (Rapamycin).

    Rapamycin/Sirolimus acts on TORC1 it is not a specific GM-CSF drug and so its affect and side-effects will be very different. Becareful when reading too much into what a drug does and does not do, sometimes it is not a direct action but a measured effect because of something else. Sometimes they do things outside normal physiological
    ranges of how the drug is used in the clinic. Too much toothpaste can do all sorts of strange things

    So you do a bit of reading and end up with vegatables.

    This is the beauty and the problem with the internet, too much information. This allows you to concoct many stories. Flavinoids what about blueberries, red wine etc, etc,

    My advice. Get your MS drugs from a neuro and not a greengrocer

  • Thanks MouseDoc.

    I was being a little flippant. But hey, flavonoids might have some natural role to play. I'm not going to bet my health on them.

    The link between IL-27, GM-CSF and EBV is interesting though, don't you think?

    Are you looking at IL-27 in the Zcharcot project?

  • I think raised levels of IL-21 in some MSers have been shown to promote secondary autoimmune disease in those treated with alemtuzumab.

  • Dear Iain O
    Yes flavinoids could be good.

    So much is interesting not enough hands to do every thing maybe if a "Howard Hughes" came to give Team G a "Howard Hughes" type grant we could do a lot more.

    Are you looking at IL-27 in Charcot project…

    Not yet…We have to get Charcot off the ground and then the Prof Gs will tell you what they are up to.

    Hopefully not long to wait…

  • Rather than celery as a way forward you may be interested in this

    Solt LA et al. Identification of a Selective RORγ Ligand That Suppresses T(H)17 Cells and Stimulates T Regulatory Cells. ACS Chem Biol. 2012 Jul 9. [Epub ahead of print]

    This is aimed at the transcription factor that drives GM-CSF

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