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      Effects of multiple-dose ponesimod, a selective S1P 1 receptor modulator, on lymphocyte subsets in healthy humans

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          Abstract

          This study investigated the effects of ponesimod, a selective S1P 1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was −1,292±340×10 6 cells/L and 275±486×10 6 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4 + T cells (CD45RA +CCR7 +) from baseline was observed only after ponesimod treatment (−113±98×10 6 cells/L, placebo: 0±18×10 6 cells/L). The number of T-cytotoxic (CD3 +CD8 +) and T-helper (CD3 +CD4 +) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4 + T-central memory (CD45RA CCR7 +) cells (−437±164×10 6 cells/L) and CD4 + T-effector memory (CD45RA CCR7 ) cells (−131±57×10 6 cells/L). In addition, ponesimod treatment led to a decrease of −228±90×10 6 cells/L of gut-homing T cells (CLA integrin β7 +). In contrast, when compared with placebo, CD8 + T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4 + cells was dramatically reduced, whereas CD8 + and NK cells were less affected, allowing the body to preserve critical viral-clearing functions.

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          Most cited references 23

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          T-cell function and migration. Two sides of the same coin.

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            Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.

            Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 and is thought to occur in response to circulatory S1P. However, the existence of an S1P gradient between lymphoid organs and blood or lymph has not been established. To further define egress requirements, we addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. We found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after THI treatment and that this treatment inhibits the S1P-degrading enzyme S1P lyase. We conclude that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target.
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              Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs.

              Secondary lymphoid organs serve as hubs for the adaptive immune system, bringing together antigen, antigen-presenting cells, and lymphocytes. Two families of G protein-coupled receptors play essential roles in lymphocyte migration through these organs: chemokine receptors and sphingosine-1-phosphate (S1P) receptors. Chemokines expressed by lymphoid stromal cells guide lymphocyte and dendritic cell movements during antigen surveillance and the initiation of adaptive immune responses. S1P receptor-1 is required for lymphocyte egress from thymus and secondary lymphoid organs and is downregulated by the immunosuppressive drug FTY720. Here, we review the steps associated with the initiation of adaptive immune responses in secondary lymphoid organs, highlighting the roles of chemokines and S1P.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                28 December 2016
                : 11
                : 123-131
                Affiliations
                [1 ]Department of Biomedical Sciences, University of Westminster, London, UK
                [2 ]Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
                [3 ]Division of Transplantation Immunology & Mucosal Biology, King’s College London, London, UK
                Author notes
                Correspondence: Pierre-Eric Juif, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland, Tel +41 61 565 8890, Fax +41 61 565 6200, Email pierre-eric.juif@ 123456actelion.com
                Article
                dddt-11-123
                10.2147/DDDT.S120399
                5207338
                © 2017 Jurcevic et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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