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FTY720 is a derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analog of sphingosine. It is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs.1 FTY720 is phosphorylated by sphingosine kinase, which then acts as a potent agonist at four of the sphingosine-1-phosphate (S1P) receptors (S1P1, S1P3, S1P4, and S1P5).2 Down-regulation of S1P1 receptors on T and B lymphocytes by FTY720 results in defective egress of these cells from spleen, lymph nodes, and Peyer’s patch.3 FTY720 also enhances the activity of the sphingosine transporter Abcb1 and the leukotriene C4 transporter Abcc1 and inhibits cytosolic phospholipase A2 activity.4,5
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1
Brinkmann, V., Pinschewer, D.D., Feng, L., et al. FTY720: Altered lymphocyte traffic results in allograft protection. Transplantation 72 764-769 (2001).
2
Brinkmann, V., Davis, M.D., Heise, C.E., et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277(24) 21453-21457 (2002).
3
Matloubian, M., Lo, C.G., Cinamon, G., et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427 355-360 (2004).
4
Honig, S.M., Fu, S., Mao, X., et al. FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. J Clin Invest 111(5) 627-637 (2003).
5
Payne, S.G., Oskeritizian, C.A., Griffiths, R., et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood 109(3) 1077-1085 (2007).
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