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:Fingolimodisasphingosine-1-phosphate(S1P)receptormodulatorapproved
for the treatment of the relapsing form of multiple sclerosis (MS). It prevents the
Results: After 3months of treatment, significant transcriptome shifts were seen in
sive MS as well.