The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases

Mao-Draayer, Yang; Sarazin, Jeffrey; Fox, David A.; Schiopu, Elena

doi:10.1016/j.clim.2016.11.008

Cited by 54 publications

(47 citation statements)

References 59 publications

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“…Further implicating memory T cells in MS are the results of treating MS patients with fingolimod (also known as FTY720), an S1P receptor (S1PR) antagonist which is thought to act by downregulating the expression of S1PR1 on lymphocytes and is now approved for the treatment of relapsing MS [184,185]. Responsiveness to S1P (via S1PRs) and S1P-dependent tissue trafficking from lymphoid tissues to inflamed tissues are complex and reviewed elsewhere [186,187].…”

Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Raphael

Joern

Forsthuber

2020

Cells

108

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CD4 + T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4 + Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4 + T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4 + tissue-resident memory T cells and of CD4 + memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4 + T cell-mediated autoimmune diseases.

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Section: Autoreactive T CM and T Em Subsets And Disease-modifying Thementioning

confidence: 99%

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Raphael

Joern

Forsthuber

2020

Cells

108

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“…Phosphorylated FTY720 binds to S1P1 with high affinity, induces receptor internalization and causes immune cells to become insensitive to S1P gradients [18]. Moreover, a series of studies have demonstrated therapeutic effects of FTY720 in animal models of other autoimmune diseases, such as psoriasis, polymyositis and lupus [23]. For example, FTY720 exhibits neuroprotective effects in CNS injury models of cerebral ischaemia [19] and spinal cord injury [20].…”

Section: Introductionmentioning

confidence: 99%

“…The dominant action of FTY720 is attributed largely to autoreactive T cell sequestration in lymph nodes [22]. Moreover, a series of studies have demonstrated therapeutic effects of FTY720 in animal models of other autoimmune diseases, such as psoriasis, polymyositis and lupus [23]. Recent studies have also reported that FTY720 significantly prevents graft rejection in renal transplantation [24] and also has notable effects on kidney ischaemia/reperfusion injury [25].…”

Section: Introductionmentioning

confidence: 99%

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

Tian

Zhang

Zhu

et al. 2017

Clinical and Experimental Immunology

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Renal fibrosis is the common final manifestation of chronic kidney diseases and usually results in end-stage renal failure. In this study, we evaluated the effect of fingolimod (FTY720), an analogue of sphingosine 1-phosphate (S1P), as a treatment for the unilateral ureteral obstruction (UUO)-induced renal fibrosis animal model. We treated mice with FTY720 at a dosage of 1 mg/kg/day by intragastric administration from day 1 until day 7. The control group received the same amount of saline. FTY720 reduced significantly the urine albumin/creatinine ratio (UACR) in treated UUO mice. FTY720 treatment also caused a significant decrease in interstitial expansion and collagen deposition in the kidney, accompanied by reduced mononuclear cell recruitment and inflammatory cytokine expression. In addition, the expression levels of the endothelial cell adhesion molecules P-selectin and vascular cell adhesion protein 1 (VCAM-1) were suppressed in the ligated kidney by FTY720 administration, suggesting reduced renal endothelial cell activation. Furthermore, in renal interstitial fibroblast normal rat kidney (NRK)-49F cells, FTY720 significantly affected transforming growth factor (TGF)-β-induced α-smooth muscle actin (SMA) expression and collagen synthesis by inhibiting both the Mothers against decapentaplegic homologue (Smad)2/3 and phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase 3 beta (PI3K/AKT/GSK3β) signalling pathways. S1P1 knock-down by siRNA reversed this effect significantly in our fibroblast cell culture model. Therefore, FTY720 attenuates renal fibrosis via two different mechanisms: first, FTY720 suppresses the synthesis of extracellular matrix in interstitial fibroblasts by interfering with TGF-β signalling; and secondly, FTY720 affects endothelial cell activation and chemokine expression, thereby reducing immune cell recruitment into the kidney.

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“…Siponimod is a second-generation sphingosine-1-phosphate receptor (S1PR) modulator selective for S1PR1 and S1PR5 (4). The first-generation S1PR modulator, fingolimod, is approved for RRMS, but failed to show efficacy in the phase III INFORMS trial for primary progressive MS (PPMS) (5).…”

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

confidence: 99%

“…It is anticipated that, similarly to fingolimod, siponimod reduces inflammation by trapping S1P-sensitive subsets of lymphocytes in lymph nodes through functional antagonism of S1PR1 (7). However, compared with fingolimod, siponimod has greater receptor (S1PR1 and S1PR5) specificity, a shorter half-life, and does not require in vivo phosphorylation for biological activity (4,8). These differences may be critical for its efficacy in SPMS; therefore, it is necessary to understand the specific immune changes associated with siponimod treatment.…”

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

confidence: 99%

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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The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases

Cited by 54 publications

References 59 publications

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

FTY720 ameliorates renal fibrosis by simultaneously affecting leucocyte recruitment and TGF-β signalling in fibroblasts

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

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