The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors*

By V. Brinkmann, Michael D. Davis, C. Heise, R. Albert, S. Cottens, R. Hof, C. Bruns, E. Prieschl, T. Baumruker, P. Hiestand and 3 more. Journal of Biological Chemistry, 2002

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Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.

Subfields: Immunology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/e5bab31e981c92cf7e8e5f5639db61b6effbda85

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Citations in the corpus

THE ALLIANCE OF SPHINGOSINE-1-PHOSPHATE AND ITS RECEPTORS IN IMMUNITY (2008, background): “A breakthrough in the understanding of its mechanism, together with a link to S1PR signalling, came with the realization that FTY720 is a sphingosine analogue that could be phosphorylated by SPHKs to produce a S1PR ligan”
Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis (2010, background): “SPHINGOSINE 1-PHOSPHATE SIGNALING IN THE CNS AND EFFECTS OF FINGOLIMOD ON NEURAL CELLS Preliminary preclinical evidence indicates that fingolimod may also have direct effects within the CNS. Fingolimod is able to cross the BBB93; after oral administration, fingolimod is found in the CNS, where S1P r”
Homing and cellular traffic in lymph nodes (2003, background): “Recent studies have shown that FTY720 is phosphorylated by sphingosine kinase to an active metabolite that resembles sphingosine-1-phosphate (S1P) and binds to four of the five known S1P receptors, S1P 1 , S1P 3 , S1P 4 and S1P 5 (also known as endothelial differentiation, sphingolipid G-protein-c”
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 (2004, background): “An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptor”
Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis (2010, background): “; however, these effects occurred at drug concentrations more than 100-fold in excess of the low nanomolar exposures required for in vivo activit”
Regulation of learning and memory by meningeal immunity: a key role for IL-4 (2010, methodology): “To that end, wild-type mice were treated daily by oral administration of 1 mg/kg FTY720, a compound that causes internalization of the sphingosine 1-phosphate receptor 1 on thymocytes and lymphocytes, thus sequestering these cells in lymph nodes and inducing peripheral lymphopenia (Brinkmann et al.,”
“Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets (2008, background): “The S1P1 receptor has been shown to regulate the recirculation of lymphocytes (Brinkmann et al., 2002; Mandala et al., 2002; Rosen et al., 2003a,b; Xie et al., 2003) and regulates their egress from secondary lymphatic organs (Matloubian et al., 2004).”