Differential effects of ponesimod, a selective S1P₁ receptor modulator, on blood-circulating human T cell subpopulations

Abstract

Ponesimod, a novel selective sphingosine-1-phosphate 1 receptor modulator in the development for the treatment of autoimmune diseases, dose-dependently reduced lymphocyte counts in peripheral blood of healthy subjects. It rapidly and transiently reduced the number of circulating T and B cells, but not natural killer cells. T lymphocyte subsets exhibited differential sensitivities with a maximum decrease from baseline ranging from 67% to 89% following high doses. Naïve T cells were more sensitive than memory T cells. CD4⁺ T cells were more sensitive than CD8⁺ T cells or CD4⁺CD25⁺ T regulatory cells. The differential effects on specialized T cell subsets may contribute to the immunomodulatory activity of ponesimod. The therapeutic potential of ponesimod has been recently shown in phase II studies of chronic plaque psoriasis and relapsing–remitting multiple sclerosis. Our data suggest that lymphocyte sequestration underlies the therapeutic potential of ponesimod in multiple autoimmune and chronic inflammatory diseases.

• Cell migration
• immune response
• lymphocyte subsets
• lymphocyte trafficking
• sphingosine 1 phosphate receptor

Acknowledgements

We thank the subjects for participation in the clinical trial and our colleagues at Actelion for many stimulating discussions. The contribution of Christian Müller, Statistical Consultancy, Basel, Switzerland is gratefully acknowledged.

Declaration of interest

Daniele D'Ambrosio and Jasper Dingemanse are full time employees of Actelion Pharmaceuticals Ltd. Patrick Brossard was a full time employee of Actelion Pharmaceuticals Ltd at the time of the study. Jörg Steinmann received funding from Actelion Pharmaceuticals Ltd for this work. This study was funded by Actelion Pharmaceuticals Ltd.