Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine‐1‐phosphate receptor modulator

Angerer, Ines Charlotte; Hecker, Michael; Koczan, Dirk; Roch, Luisa; Friess, Jörg; Rüge, Annelen; Fitzner, Brit; Boxberger, Nina; Schröder, I; Flechtner, Kristin; Thiesen, Hans‐Juergen; Winkelmann, Alexander; Meister, Stefanie; Zettl, Uwe K.

doi:10.1111/cns.12793

Cited by 20 publications

(20 citation statements)

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“…The discrepancy may be related to the clinical population, as we examined SPMS participants. 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).…”

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

confidence: 78%

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

confidence: 78%

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

Wu¹,

Mills²,

Wang³

et al. 2020

JCI Insight

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“…Clinical heterogeneous response to different treatments exists in MS patients, possibly partially due to the heterogeneity of MS pathology. This is why an exhaustive analysis of the immunological background of the patients and knowledge on their ability to respond to different therapeutic alternatives is still needed . We examined in the present study changes in leukocyte subpopulations and their association with clinical and brain MRI activity in RRMS patients before and during 1 year of follow‐up under fingolimod treatment.…”

Section: Discussionmentioning

confidence: 99%

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients

et al. 2018

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“…We have performed an independent validation of our approach using a “validation dataset” (see methods) including adipocytes, progenitor cells (CD45 - CD34 + CD31 - ) and monocytes/macrophages (CD45 + CD14 + ) directly isolated from adipose tissue across 19 individuals (10 control and 9 obese) [10] and B cells, CD4 + T cells, CD8 + T cells, natural killer cells, and monocytes directly isolated from blood [11]. We use this validation dataset to evaluate the gene expression deconvolution approach on isolated cell types and to test the specificity of the proposed primary markers identified by CellMaDe.…”

Section: Resultsmentioning

confidence: 99%

Adipose tissue in health and disease through the lens of its building blocks

Lenz

Arts

Peeters

et al. 2018

Preprint

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BackgroundHighly specialized cells work in synergy forming tissues to perform functions required for the survival of organisms. Understanding this tissue-specific cellular heterogeneity and homeostasis is essential to comprehend the development of diseases within the tissue and also for developing regenerative therapies. Cellular subpopulations in the adipose tissue have been related to disease development, but efforts towards characterizing the adipose tissue cell type composition are limited due to lack of robust cell surface markers, limited access to tissue samples, and the labor-intensive process required to identify them.ResultsWe propose a framework, identifying cellular heterogeneity while providing state-of-the-art cellular markers for each cell type present in tissues using transcriptomics level analysis. We validate our approach with an independent dataset and present the most comprehensive study of adipose tissue cell type composition to date, determining the relative amounts of 21 different cell types in 779 adipose tissue samples detailing differences across four adipose tissue depots, between genders, across ranges of BMI and in different stages of type-2 diabetes. We also highlight the heterogeneity in reported marker-based studies of adipose tissue cell type composition and provide novel cellular markers to distinguish different cell types within the adipose tissue.ConclusionsOur study provides a systematic framework for studying cell type composition in a given tissue and valuable insights into adipose tissue cell type heterogeneity in health and disease.

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Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine‐1‐phosphate receptor modulator

Cited by 20 publications

References 53 publications

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

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

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients

Adipose tissue in health and disease through the lens of its building blocks

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