Fingolimod affects white blood cells, but really targets all B cells

Is Fingolimod really B cell non-selective depletor?

Angerer IC, Hecker M, Koczan D, Roch L, Friess J, Rüge A, Fitzner B, Boxberger N, Schröder I, Flechtner K, Thiesen HJ, Winkelmann A, Meister S, Zettl UK.
Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine-1-phosphate receptor modulator.
CNS Neurosci Ther. 2018 Jan 3. doi: 10.1111/cns.12793.

Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of the relapsing form of multiple sclerosis (MS). It prevents the egress of lymphocyte subpopulations from lymphoid tissues into the circulation. Here, we explored the broad effects of fingolimod on gene expression in different immune cell subsets.
METHODS: Utilizing 150 high-resolution microarrays from Affymetrix, we obtained the transcriptome profiles of 5 cell populations, which were separated from the peripheral blood of MS patients prior to and following oral administration of fingolimod.
RESULTS: After 3 months of treatment, significant transcriptome shifts were seen in CD4+ and CD8+ cells, which is mainly attributable to the selective homing of naive T cells and central memory T cells. Although the number of B cells was greatly reduced in the blood of fingolimod-treated MS patients, the analysis of differential expression in CD19+ cells identified only a small set of 42 genes, which indicated a slightly higher frequency of transitional B cells.The transcriptome signatures of CD14+ monocytes and CD56+ natural killer cells were not affected.
CONCLUSION:Our study corroborates changes in the composition of circulating immune cells in response to fingolimod and delineates the respective implications at the RNA level. Our data may be valuable for comparing the effects of novel S1P receptor modulating agents, which may be a therapeutic option for patients with secondary progressive MS as well.

This study looked at the gene expression by lymphocytes after treatment with fingolimod. There were massive changes in the T cell populations, notably about 6,500 genes were differentially expressed in CD4 cells, so the populations after fingolimod are very different. We know that because fingolimod blocks naive T cells and central memory cells from entering the blood.

However, only 42 genes were deferentially expressed in B cells. 

This is amazing considering this population was reduced by almost 90% after 3 months. 

The implications must be that fingolimod reduces all B cell subsets by a similar amount and that there is limited selectivity for memory B cells, but it just gets rid of B cells out of the blood.

One of the most affected genes was the ZEB2, a transcriptional repressor that contributes to maintenance of EBV latency by inhibiting lytic reactivation in B cells, which is just what you want if you are a B memory cell. Another was MYBL1 which is usually highly expressed in germinal centre cells.

Our study corroborates changes in the composition of circulating immune cells in response to fingolimod and delineates the respective implications at the RNA level. Our data may be valuable for comparing the effects of novel S1P receptor modulating agents, which may be a therapeutic option for patients with secondary progressive MS as well.Aims:Fingolimodisasphingosine-1-phosphate(S1P)receptormodulatorapproved
for the treatment of the relapsing form of multiple sclerosis (MS). It prevents the
cell subsets.
Results: After 3months of treatment, significant transcriptome shifts were seen in
sive MS as well.

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  • Good-good, but also a trap for pwMS in Europe cause EMA protocols are ******* conservative, and demand a normal lymprange. What does it mean: 10% chance for disabling rebound.

  • "This is amazing considering this population was reduced by almost 90% after 3 months. "

    Same in cd4+ …

    Its a coincidence? 🙂


    • In-depth characterization of CD24highCD38high
      transitional human B cells reveals different
      regulatory profiles

      Anergic-like T3 B cells regulate T-cell proliferation. In
      the next set of experiments, proliferation of sorted CD41 T cells
      was studied by using flow cytometry at day 4 in the presence or
      absence of sorted transitional B-cell subsets (Fig 6, B). T1 and
      CD271 transitional B cells were unable to suppress T-cell
      proliferation. In contrast, T2 and T3 cells exhibited a significant
      ability to reduce CD41 T-cell proliferation. Interestingly, the
      T3 B-cell subset showed the highest reproducibility (P 5.0078)
      in the ability to reduce T-cell proliferation among different
      donors when compared with T2 B cells (P 5 .027), suggesting
      that the latter might be composed of different functional
      These observations demonstrate that transitional B-cell subsets
      have differential abilities to regulate T-cell responses.

      Idiopathic CD4 T lymphocytopenia (ICL)
      is a rare heterogeneous disorder defined
      by CD4 T-cell counts below 300 cells/ L
      in the absence of human immunodeficiency
      virus (HIV) infection or other known
      immune deficiency disorders. Here, we
      report the expansion of immature/
      transitional B cells in patients with ICL,
      which is associated with elevated serum
      levels of IL-7. Both the percentage of
      immature/transitional B cells and levels
      of IL-7 were inversely correlated with levels
      of CD4 T-cell counts and directly
      correlated to each other. Further analyses
      of B cells indicated that, in contrast to the
      activating effects of HIV disease on mature
      B cells, the expansion of immature/
      transitional B cells in patients with ICL
      occurred at the expense of memory
      B cells.

      (Blood. 2007;109:

      Cd4+t cells and B cells talk to each other?


    • Interestingly you should measure treatment response not on the b cell but on the cd4+ depletion

      After all anti cd20 drug affect cd4+ t cell pool

      The present study shows that a
      decrease in CD4+ T-cell counts occurred repeatedly
      along with clinical response in patients who received up
      to seven cycles of RTX. A slightly additive effect of
      repeated treatment was seen, with the mean posttreatment
      CD4+ T-cell count gradually reaching the
      lower limit of the normal range

      contrast, an RTX-induced CD4+ T-cell decrease was
      followed by complete recovery of the circulating CD4+
      T-cell pool at the end of each cycle. The time to CD4+
      T cell recovery may vary across patients and may relate
      to the time to relapse.

      Also we previously reported that
      there was a greater decrease in the CD4+ T-cell count in
      patients whose time to retreatment was >12 months
      than in those whose time to retreatment was <12 months
      [11]. The assumption that CD4 could be a valuable
      marker is based on the coincidence between the clinician’s
      decision whether to retreat and the CD4 recovery
      It is indeed very apparent that recovery of CD4+ cells
      occurs at the time of the relapse. Taken together, these
      results show that in patients with RA receiving RTX,
      disease activity is more closely related to CD4+ T-cell
      variations than to B-cell variations, suggesting that monitoring
      CD4+ T cells might be more relevant for predicting
      disease relapse. The present results reopen the issue
      of re-treatment timing, and suggest that a scheme of
      RTX administration based on CD4+ T-cell counts might
      anticipate and eventually avoid disease relapse

      Repeated decrease of CD4+ T-cell counts
      in patients with rheumatoid arthritis over
      multiple cycles of rituximab treatment

      DOI 10.1186/s13075-016-1152-5

    • They are hand in hand… 😉

      You deplete one and the other goes down (or dont mature in the case of b cells)


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