Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with SLE (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod/Gilenya in relapsing forms of multiple sclerosis, supporting therapeutic concept of sphingosine 1-phosphate for the treatment of autoimmune disorders.
In this study, the mode of action of cenerimod was studied in primary human lymphocytes in a series of in vitro experiments including S1P1 receptor internalization and a newly developed real-time migration assay. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the influence of GC on S1P1 receptor expression and function were studied.
Methods: Primary human T lymphocytes from healthy donors were isolated from whole blood cultured with different concentrations of cenerimod to measure S1P1 receptor internalization and sphingosine 1-phosphate (S1P)-directed chemotaxis using flow cytometry and real-time migration assays. In a second series of experiments, the effect of different concentrations of GC (prednisolone and dexamethasone) on S1P1 receptor expression was evaluated. Finally, the effect of physiological concentrations of GCs on cenerimod activity in the receptor internalization and migration assay were tested.
Results: In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human CD4 and CD8 T lymphocytes. Cenerimod also blocked migration of activated T lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Culturing of T cells with GC lead to a slight dose dependent decrease of cell surface expression of S1P1 receptor on CD8 and CD4 T lymphocytes. Importantly, physiological concentrations of GC did not affect the activity of cenerimod in the receptor internalization or the migration assay.
Conclusion: These results show that cenerimod by modulating S1P1 blocks T lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod and GC.
To cite this abstract in AMA style:Kulig P, Murphy M, Keller M. In Vitro Characterization of the Effect of Cenerimod, a Potent and Selective Sphingosine 1-Phosphate Receptor 1 (S1P1) Modulator, on S1P1 Receptor Expression, Receptor Internalization, and Migration of Primary Human T Cells in the Presence or Absence of Glucocorticoids [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/in-vitro-characterization-of-the-effect-of-cenerimod-a-potent-and-selective-sphingosine-1-phosphate-receptor-1-s1p1-modulator-on-s1p1-receptor-expression-receptor-internalization-and-migration-o/. Accessed February 20, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vitro-characterization-of-the-effect-of-cenerimod-a-potent-and-selective-sphingosine-1-phosphate-receptor-1-s1p1-modulator-on-s1p1-receptor-expression-receptor-internalization-and-migration-o/