Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists

Abstract

Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

“…The novel immunomodulator FTY720 causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, which results in a decrease of recirculating lymphocytes and reduced infiltration into sites of antigen challenge [1][2][3]. This mechanism of action has been shown to be highly effective in suppressing allograft rejection and autoimmune diseases in a variety of animal models [4,5] and in initial clinical trials [6,7].…”

“…The S1PR have been identified, their isoformspecific differential tissue and cellular expression and their molecular signaling pathways have been characterized, and the elicited cellular responses have been examined [8,[14][15][16]. S1P [1][2][3] are widely distributed, whereas S1P 4 is mainly expressed in the lymphoid tissue, and S1P 5 is restricted to the nervous system. Expression of S1PR in the immune system has been shown to vary among CD4 + and CD8 + T cells, B cells and monocytes [17].…”

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials

“…Among these four receptors, S1P 1 has been shown to be critically involved in lymphocyte trafficking and agonism of this receptor is responsible for the peripheral blood lymphopenia believed to be key to the efficacy seen with 1. 2,3 Clinical studies have demonstrated a side effect profile of 1 that includes cardiovascular effects (transient bradycardia, sustained blood pressure elevation) as well as a decline in pulmonary function. 4 In rodent studies, S1P 3 activity was shown to play a role in some of the observed acute toxicity of nonselective S1P receptor agonists, including bradycardia, hypertension, and bronchoconstriction.…”

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator

“…7 FTY720 is phosphorylated in vivo by sphingosine kinase to the active metabolite FTY720-phosphate ( Figure 1). 8,9 The latter binds with nanomolar affinity as an agonist at four of the five S1P receptors, namely, S1P 1 , S1P 3 , S1P 4 , and S1P 5 . 8,9 Interestingly, FTY720-phosphate was shown to elicit its immunosuppressive effect through functionally antagonizing S1P 1 signaling pathway.…”

“…8,9 The latter binds with nanomolar affinity as an agonist at four of the five S1P receptors, namely, S1P 1 , S1P 3 , S1P 4 , and S1P 5 . 8,9 Interestingly, FTY720-phosphate was shown to elicit its immunosuppressive effect through functionally antagonizing S1P 1 signaling pathway. 10,11 It induces rapid and persistent internalization of the S1P 1 receptor that is required for lymphocyte egress from the secondary lymphoid organs.…”