Abstract
Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P1) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including T and B lymphocytes) in the bloodstream and inflamed tissues, making them an effective therapeutic concept for autoimmune disorders. Although the effect of S1P receptor modulators in reducing circulating lymphocytes is well documented, the precise molecular role of the S1P1 receptor on these cell types is not fully understood. In this study, the mode of action of cenerimod on human primary lymphocytes in different activation states was investigated focusing on their chemotactic behavior towards S1P in real-time, concomitant to S1P1 receptor expression and internalization dynamics. Here, we show that cenerimod effectively prevents T and B cell migration in a concentration-dependent manner. Interestingly, while T cell activation led to strong S1P1 re-expression and enhanced migration; in B cells, an enhanced migration capacity and S1P1 receptor surface expression was observed in an unstimulated state. Importantly, concomitant treatment with glucocorticoids (GCs), a frequently used treatment for autoimmune disorders, had no impact on the inhibitory activity of cenerimod on lymphocytes.
Highlights
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that acts as a ligand on a group of five G-protein-coupled receptors sphingosine 1-phosphate receptor 1 (S1P1)–S1P5
The results obtained with cenerimod are in line with results from Strasser et al on lymphocytes from healthy subjects and patients with systemic lupus erythematosus (SLE) [9]
This supports the model of CD69 mediating transient lymphocyte retention and subsequent egress mediated by re-expressed high levels of S1P1 receptor upon antigeninduced T cell activation
Summary
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that acts as a ligand on a group of five G-protein-coupled receptors S1P1–S1P5. Various other selective S1PR modulators followed in the area of MS (ozanimod, ponesimod and siponimod) and ulcerative colitis (UC; ozanimod) These modulators act as functional antagonists on the S1P1 receptor by leading to sustained receptor internalization and desensitization. Systemic lupus erythematosus (SLE) is another indication for which this mode of action may be an appropriate means of intervention This autoimmune disease with a high unmet medical need can affect virtually any organ of the body ranging from mild to life-threatening manifestations including irreversible organ(s) dysfunction and reduced life span. It has been shown that T and B lymphocytes play a major role in disease development via autoantibody production and tissue infiltration, making SLE an attractive target for S1P1 receptor modulators [6,7]. As GCs are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GCs on S1P1 receptor expression and function was investigated
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