Biomarkers. Response to Fingolimod can be predicted.

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frodo
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Biomarkers. Response to Fingolimod can be predicted.

Post by frodo » Thu Apr 19, 2018 12:31 pm

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients

https://onlinelibrary.wiley.com/doi/abs ... /cns.12851

Summary

Fingolimod, an orally active immunomodulatory drug for relapsing‐remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine‐1‐phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune‐monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod.

Methods


Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow‐up in 40 RRMS patients starting fingolimod therapy.

Results

Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg: 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg: 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed.

Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively [P < 0.001]).

Conclusion

The results support that immune‐monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.

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Response to Fingolimod can be predicted 2: GPCRs

Post by frodo » Mon Jan 20, 2020 9:09 am

Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor

https://www.nature.com/articles/s42003-020-0752-4

The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors.

Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1, a class A GPCR, is in allosteric communication with both the β-arrestin-binding C-terminal tail, and a receptor surface involved in oligomerization. We show that S1PR1 oligomers are required for full response to different agonists and ligand-specific association with arrestins, dictating the downstream signalling kinetics.

We reveal that the active form of the immunomodulatory drug fingolimod, FTY720-P, selectively harnesses both these intramolecular networks to efficiently recruit β-arrestins in a stable interaction with the receptor, promoting deep S1PR1 internalization and simultaneously abrogating ERK1/2 phosphorylation.

Our results define a molecular basis for the efficacy of fingolimod for people with multiple sclerosis, and attest that GPCR signalling can be further fine-tuned by the oligomeric state.

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Re: Biomarkers. Response to Fingolimod can be predicted.

Post by frodo » Tue May 19, 2020 4:52 am

New biomarker for fingolimod: CD56bright

https://www.mdpi.com/2077-0383/9/5/1450/htm

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, which leads, in many cases, to irreversible disability. More than 15 disease-modifying treatments (DMTs) are available for the treatment of MS. Clinical activity or activity at magnetic resonance imaging (MRI) are now used to assess the efficacy of DMTs, but are negative prognostic factors per se. Therefore, a biomarker permitting us to identify patients who respond to treatment before they develop clinical/radiological signs of MS activity would be of high importance. The number of circulating CD56bright natural killer (NK) cells may be such a biomarker. CD56bright NK cells are a regulatory immune population belonging to the innate immune system. The number of CD56bright NK cells increases upon treatment with interferon-beta, alemtuzumab, dimethyl fumarate, after autologous hematopoietic stem cell transplantation, and is higher in those who respond to fingolimod. In some cases, an increased number of CD56bright NK cells is associated with an increase in their regulatory function. In the current review, we will evaluate the known effect on CD56bright NK cells of DMTs for MS, and will discuss their possible role as a biomarker for treatment response in MS.

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