How does fingolimod work?

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We have been told that fingolimod inhibits the migration of T cells out of lymph nodes as a working mechanism, but I would also argue that it inhibits B cells migration but that is not all. it also inhibits macrophage function. So if we believe that there are bad macrophages it should be beneficial.

Sferruzza G, Clarelli F, Mascia E, Ferrè L, Ottoboni L, Sorosina M, Santoro S, Moiola L, Martinelli V, Comi G, Martinelli Boneschi F, Filippi M, Provero P, Esposito F. Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients. Mol Neurobiol. 2021 Jun 28. doi: 10.1007/s12035-021-02465-z

Fingolimod (FTY), a second-line oral drug approved for relapsing remitting Multiple Sclerosis (RRMS) acts in preventing lymphocyte migration outside lymph nodes; moreover, several lines of evidence suggest that it also inhibits myeloid (macrophages) cell activation. In this study, we investigated the transcriptional changes induced by FTY in monocytes in order to better elucidate its mechanism of action. CD14+ monocytes were collected from 24 RRMS patients sampled at baseline and after 6 months of treatment and RNA profiles were obtained through next-generation sequencing. We conducted pathway and sub-paths analysis, followed by centrality analysis of cell-specific interactomes on differentially expressed genes (DEGs). We investigated also the predictive role of baseline monocyte transcription profile in influencing the response to FTY therapy. We observed a marked down-regulation effect (60 down-regulated vs. 0 up-regulated genes). Most of the down-regulated DEGs resulted related with monocyte activation and migration like IL7R, CCR7 and the Wnt signaling mediators LEF1 and TCF7. The involvement of Wnt signaling was also confirmed by subpaths analyses. Furthermore, pathway and network analyses showed an involvement of processes related to immune function and cell migration. Baseline transcriptional profile of the HLA class II gene HLA-DQA1 and HLA-DPA1 were associated with evidence of disease activity after 2 years of treatment. Our data support the evidence that FTY induces major transcriptional changes in monocytes, mainly regarding genes involved in cell trafficking and immune cell activation. The baseline transcriptional levels of genes associated with antigen presenting function were associated with disease activity after 2 years of FTY treatment.

So here we find an inhibitory effect on monocyte (blood macrophage) function. How does fingolimod do this? We know that lymphocyte migration is controlled by S1R1 receptor, but fingolimod not only binds to S1PR1, but also to S1PR3,4,5, Unlike lymphocytes macophages do not seem to express too much S1PR1 (see above), however they do express other receptors such as S1PR4 (e.g. light blue). Why ask? Because the implication is that fingolimod inhibits macrophage function. Is this mediated by SP1R1 or S1PR4? I don’t know. But it is important to know…Why?

http://www.biogps.org. S1PR1 (left) S1PR4 (right) RNA expression in primary cell atlas

Well Siponimod, Ozanimod and Ponesimod block S1PR1 and S1PR5 but not S1PR3 or 4. So if fingolimod blocks macrophage antigen presentation because of effects on S1PR4, then this effect won’t happen with siponimod, ozanimod or ponesimod.

Now I ask. Is macrophage (red above and cyan above) and dendritic cell (blue above) antigen presentation required for the generation of a SARS-COVID-2 vaccine. Because if it is, it may explain why fingolimod inhibits the COVID-19 vaccine response. But it this is an S1PR4 effect then it wont be caused by some of the newer imods,

So I wonder what the COVID-19 vaccine reponse to siponimod may be.

So hopefully the Novarsians will give us the anwser.

CoI Multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

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MouseDoctor

3 comments

    • years with regard to microglia. This is shown in animals with bone marrow transplants, the rest of the immune system changed the microglia did not..although it is complicated as there is evidence of non bone marrow associated renewal

  • I see the JCVI are recommending booster shots from September onwards so good news for people on Fingolimod and Ocrevus I presume as the immunosupressed are going to be done first
    Hugo Gye
    @HugoGye
    BREAKING

    JCVI advises that covid boosters should be given from September 2021 along with flu jabs

    Stage 1: 3rd doses for immunosuppressed; older care residents; all 70+; clinically extremely vulnerable; health/care workers

    Stage 2: 3rd doses for all 50+; vulnerable under-50s

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