Research: GM-CSF a Target for T cells


You asked aboutCodarri et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560-7. 


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found out that IL-12 was not important for the development of autoimmunity in mice, but IL-23 then Th1 cells had to be superceded.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 it..at 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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