Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Torres, Ivo; Garcı́a, C.; Marconi, Marco; García-Grande, Aránzazu; Rodríguez‐Esparragoza, Luis; Elvira, Vı́ctor; Ramil, Elvira; Campos-Ruíz, Lucía; García-Hernández, Ruth; Al‐Shahrour, Fátima; Fustero-Torre, Coral; Sánchez-Sanz, Alicia; García‐Merino, Antonio; López, A.J. Sánchez

doi:10.3389/fimmu.2018.01693

Cited by 32 publications

(43 citation statements)

References 69 publications

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“…Our study included higher numbers of Active patients (18 versus 8) selected using different criteria and also defined RTE differently. Moreno-Torres and colleagues 33 reported a higher pre-treatment CD56 bright NK cell frequency in patients who were subsequently stable versus active on FTY; a finding not replicated here. A cross-sectional study found higher CD56+ T-cell frequencies in FTY-treated versus untreated patients, and an even higher frequency of these cells during relapse in 4 patients 34 .…”

Section: Discussioncontrasting

confidence: 71%

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Ghadiri

Rezk

et al. 2020

Sci Rep

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Bar-or 1,3* Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as 'Active' or 'Stable' based on clinical and/ or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre-and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + t cells, CD56 dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.

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Section: Discussioncontrasting

confidence: 71%

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Ghadiri

Rezk

et al. 2020

Sci Rep

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“…As expected, genes related to the mechanism of action of an S1PR modulator, such as S1PR1 and CCR7, were downregulated, as reported with fingolimod (13,14). Furthermore, we found that siponimod exerted an antiinflammatory effect through the downregulation of AKT3, CD19, CD40, CD40L, IL23A, CXCR5, IL2RA, IL7R, IL23A, IL21R, IL11RA, IL6ST, CR2, and IRF4 genes, which is similar to what has been observed in RRMS patients treated with fingolimod (15). Consistent with the microarray analysis, significant reductions in the CD19 + B cell and CD4 + T cell populations were detected via immunophenotyping analysis.…”

Section: L I N I C a L M E D I C I N Esupporting

confidence: 89%

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis

Wu¹,

Mills²,

Wang³

et al. 2020

JCI Insight

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5 The AMS04 Study Group is detailed in the Supplemental Acknowledgments. BACKGROUND. Siponimod (BAF312) is a selective sphingosine-1-phosphate receptor 1 and 5 (S1PR1, S1PR5) modulator recently approved for active secondary progressive multiple sclerosis (SPMS). The immunomodulatory effects of siponimod in SPMS have not been previously described. METHODS. We conducted a multicentered, randomized, double-blind, placebo-controlled AMS04 mechanistic study with 36 SPMS participants enrolled in the EXPAND trial. Gene expression profiles were analyzed using RNA derived from whole blood with Affymetrix Human Gene ST 2.1 microarray technology. We performed flow cytometry-based assays to analyze the immune cell composition and microarray gene expression analysis on peripheral blood from siponimod-treated participants with SPMS relative to baseline and placebo during the first-year randomization phase. RESULTS. Microarray analysis showed that immune-associated genes involved in T and B cell activation and receptor signaling were largely decreased by siponimod, which is consistent with the reduction in CD4 + T cells, CD8 + T cells, and B cells. Flow cytometric analysis showed that within the remaining lymphocyte subsets there was a reduction in the frequencies of CD4 + and CD8 + naive T cells and central memory cells, while T effector memory cells, antiinflammatory Th2, and T regulatory cells (Tregs) were enriched. Transitional regulatory B cells (CD24 hi CD38 hi) and B1 cell subsets (CD43 + CD27 +) were enriched, shifting the balance in favor of regulatory B cells over memory B cells. The proregulatory shift driven by siponimod treatment included a higher proliferative potential of Tregs compared with non-Tregs, and upregulated expression of PD-1 on Tregs. Additionally, a positive correlation was found between Tregs and regulatory B cells in siponimodtreated participants. CONCLUSION. The shift toward an antiinflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS. TRIAL REGISTRATION. NCT02330965.

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“…Interestingly, immunophenotyping analyses have shown that fingolimod and siponimod induce a reduction in circulating CD4+ T cells, CD8+ T cells (specifically a selective reduction of naïve and central memory T cells with a relative increase of peripheral effector memory T cells), as well as B cells, in patients with RRMS and SPMS, respectively [90][91][92]. Gene expression studies have also shown reductions in the expression of key inflammation-related genes with fingolimod in patients with RRMS [93] and with siponimod in patients with SPMS [91]. Additionally, siponimod was shown to shift the immune system toward an anti-inflammatory and suppressive homeostatic state through enrichment of regulatory T cells, transitional regulatory B cells and B1 subsets, possibly contributing to the clinical efficacy of siponimod in SPMS [91].…”

Section: S1pr Modulation and Effects On Lymphocytesmentioning

confidence: 99%

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

107

146

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Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Electronic supplementary material The online version of this article (10.1007/s40265-020-01431-8) contains supplementary material, which is available to authorized users.

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Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Cited by 32 publications

References 69 publications

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Pre-treatment T-cell subsets associate with fingolimod treatment responsiveness in multiple sclerosis

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

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