Lymphopenia induced by a novel selective S1P1 antagonist structurally unrelated to S1P

Abstract: Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P1) and participates in many pathological conditions. We developed a novel type S1P1-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P1 resulting in reduced signaling downstream of S1P1, including GTPγS-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P1-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P1 antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P1 agonists on lymphocyte sequestration results from their functional antagonism. [Copyright &y& Elsevier]