When they looked in the CNS of animals treated for ages with fingolimod they found reduced activation of the innate immune system
Then the study looks at the effect of the drug on isolated astrocytes and importantly human astrocytes and finds a number of pro-inflammatory genes down regulated, some are upregulated like IL-10 and neurotoxicity goes down, through blockade of one of the central transcription factors controlling inflammatory signalling.
So they suggest that fingolimod is going to protect nerves and fingolimod will stop secondary progressive MS.
It is however pointed out that fingolimod actually failed to affect primary progressive MS, but there was some effect in secondary progressive MS with siponimod. This study sponsored by Novartis, makes it look promising. Maybe Siponimod works via blocking astrocytes
However, whilst the message in the paper is crystal clear, the supporting EAE is perhaps not quite as clear cut as it seems.
We have a read round the subject because if this study highlights a quick way to find treatments for progressive MS, we need to be doing this.
However, NOD mice develop diabetes and so are classed as a harmful mutants, creating more problems to use them. Generally however the adjuvants used to cause EAE, block NOD mice from becoming diabetic. Anyway back to the study.
First thing to be said, in contrast to the suggestion tin the paper, there were studies looking at chronic EAE, years before this current report.
It was not mentioned...wonder why I get grumpy:-)
Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011;17(8):939-48
In a similar experiment in ABH mice treated with fingolimod, there was a marked effect on disease with treated animals. So the results look the similar but perhaps the treatment effect was much more marked.
There was less nerve damage and less myelin loss, however the interpretation was somewhat different.
It was not that this was about astrocytes, they were not looked at, but it was that fingolimod was blocking relapses.
This is because the model in relapsing progressive, where relapses occur but animals recover with increasing deficit. The relapses burn out after 3-4 attacks and you get a very slow worsening of disease (secondary progression starting months after disease onset) that does not respond to T cell inhibition and incidentally did not respond to fingolimod treatment, so suggesting that fingolimod may fail in progressive MS, which it was subsequently shown to do.
ProfG has mentioned the importance of "Thinkhand" as a treatment option and has reported that ocrelizumab and natalizumab have protected hand function in the none hole peg test. However the trials with S1P1 modulators have not reported effects on hand function. Why not?
It must tell us something but what?
Anyway in the first study (above) the beasties were treated from day 40 and "FTY720 ameliorated progressive NOD EAE without significant effects on the peripheral T-cell response". So we have a difference in World View.
However, this was measured by monitoring T cell responses from the spleen. However, as the response of the drug is to keep cells in lymphoid organs, would we be expecting a decrease in T cell function..maybe if we looked at the blood there may had been an effect. However the inference is clear this is workig via blockade of astrocytes and not T cells