The novel sphingosine-1-phosphate receptors antagonist AD2900 affects lymphocyte activation and inhibits T-cell entry into the lymph nodes
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Jing Song1, Arie Dagan2, Zhanna Yakhtin1, Shimon Gatt2, Sean Riley3, Hugh Rosen3, Reuven Or1,* and Osnat Almogi-Hazan1,*
1Department of Bone Marrow Transplantation, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
2Department of Biochemistry and Molecular Biology, Hebrew University-Hadassah School of Medicine, Jerusalem, Israel
3Department of Chemical Physiology, The Scripps Research Institute, California, USA
*These authors have contributed equally to this work
Reuven Or, email: email@example.com
Keywords: sphingosine-1-phosphate, lymphocyte localization, S1PR, lymphocyte activation, T cells
Received: November 14, 2016 Accepted: May 28, 2017 Published: June 27, 2017
Sphingolipid derivatives play key roles in immune cell migration and function. Synthetic sphingolipid analogues are used as therapeutics to intervene various inflammatory and malignant conditions. We hypothesize that different analogs have different effects on immune cells and therefore can be used as treatment for specific diseases. This study examines the properties of the novel synthetic sphingolipid analog, AD2900, and its effects on immune cell activation and lymphocyte localization in homeostasis. AD2900 is an antagonist for all sphingosine-1-phosphate (S1P) receptors. It demonstrates a significant inhibitory effect on the proliferation of activated human peripheral blood mononuclear cells, which is dependent on cAMP reduction and calcium signal transduction but not on phospholipase C activation. AD2900 causes a significant but reversible downregulation of S1P1 expression on the cell surface. AD2900 administration to C57BL/6J mice leads to the accumulation of T cells in the blood and spleen and in turn reduces T-cell number in the lymph nodes. Moreover, AD2900 treatment shows significant effects on the localization of T-cell subpopulations. These results demonstrate the key roles of S1P in T-cell trafficking in a steady state and suggest a potential clinical application for AD2900. Notably, this sphingolipid analog does not cause a severe lymphopenia. The clinical effect of AD2900 in hemato-oncologic diseases and immune-related diseases needs further investigation.
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