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

Abstract

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.

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

“…In addition, S1P acting at S1PR 1 inhibits the function of regulatory T cells, by blocking the differentiation of precursor cells and the function of mature cells, and so reduces their suppression of Th17 formation [89]. 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].…”

“…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].…”

“…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]. The time taken for lymphocyte counts to fall after treatment initiation, and the time taken for them to recover following treatment cessation, are summarised for various S1PR modulators in Table 1 [55].…”

Differential Effects of MS Therapeutics on B Cells—Implications for Their Use and Failure in AQP4-Positive NMOSD Patients

“…Siponimod, a direct successor of fingolimod for oral use with a similar mode of action was recently approved for the treatment of adults with secondary progressive MS with active disease evidenced by relapses or imaging features of inflammatory activity [ 81 ]. A recent study showed that siponimod reduces the total lymphocyte and B cell count, while increasing the proportion of regulatory B cells and decreasing the frequency of memory B cells [ 82 ]. In a murine myasthenia gravis model, no change was observed in either antibody titers or total or antigen-specific plasma cell populations after treatment [ 83 ].…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…In SPMS patients, RNA derived from whole-blood samples of siponimod-treated patients have reduced expression levels of immune-associated genes involved in T-and B-cell activation and receptor signaling, which is consistent with the reduction in CD4+ T cells, CD8+ T cells, and B cells. Flow cytometric analyses showed that, within the remaining lymphocyte subsets, the incidences of CD4 + and CD8 + naive T cells were reduced, while anti-inflammatory Th2 and T regulatory cells (Tregs) were enriched [120], indicating a shift towards an anti-inflammatory and suppressive homeostatic immune system that can contribute to the clinical effectiveness of siponimod in SPMS.…”