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Science 296 (5566): 346-349

Copyright © 2002 by the American Association for the Advancement of Science

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

Suzanne Mandala,1 Richard Hajdu,1 James Bergstrom,1 Elizabeth Quackenbush,2 Jenny Xie,2 James Milligan,1 Rosemary Thornton,1 Gan-Ju Shei,1 Deborah Card,1 CarolAnn Keohane,1 Mark Rosenbach,1 Jeffrey Hale,3 Christopher L. Lynch,3 Kathleen Rupprecht,3 William Parsons,3 Hugh Rosen1*

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.

Departments of
1 Immunology and Rheumatology,
2 zaff;2>Pharmacology, and
3 zaff;3>Medicinal Chemistry, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA.
*   To whom correspondence should be addressed. E-mail: hugh_rosen{at}merck.com

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J.-J. Liao, M.-C. Huang, K. Fast, K. Gundling, M. Yadav, J. R. Van Brocklyn, M. R. Wabl, and E. J. Goetzl (2009)
FASEB J 23, 1786-1796
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Targeting Protein Serine/Threonine Phosphatases for Drug Development.
J. L. McConnell and B. E. Wadzinski (2009)
Mol. Pharmacol. 75, 1249-1261
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G Protein-Coupled Receptors as Potential Drug Targets for Lymphangiogenesis and Lymphatic Vascular Diseases.
W. P. Dunworth and K. M. Caron (2009)
Arterioscler Thromb Vasc Biol 29, 650-656
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Sphingosine-1-phosphate and modulation of vascular tone.
J. Igarashi and T. Michel (2009)
Cardiovasc Res 82, 212-220
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Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection.
K. Sattler and B. Levkau (2009)
Cardiovasc Res 82, 201-211
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Lysophospholipid receptors in vertebrate development, physiology, and pathology.
A. Skoura and T. Hla (2009)
J. Lipid Res. 50, S293-S298
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Accumulation of Fingolimod (FTY720) in Lymphoid Tissues Contributes to Prolonged Efficacy.
S.-C. Sensken, C. Bode, and M. H. Graler (2009)
J. Pharmacol. Exp. Ther. 328, 963-969
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Inhibition of CCR6 Function Reduces the Severity of Experimental Autoimmune Encephalomyelitis via Effects on the Priming Phase of the Immune Response.
A. Liston, R. E. Kohler, S. Townley, S. Haylock-Jacobs, I. Comerford, A. C. Caon, J. Webster, J. M. Harrison, J. Swann, I. Clark-Lewis, et al. (2009)
J. Immunol. 182, 3121-3130
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A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection.
D. Marsolais, B. Hahm, K. B. Walsh, K. H. Edelmann, D. McGavern, Y. Hatta, Y. Kawaoka, H. Rosen, and M. B. A. Oldstone (2009)
PNAS 106, 1560-1565
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Oral fingolimod (FTY720) in multiple sclerosis: Two-year results of a phase II extension study.
P. O'Connor, G. Comi, X. Montalban, J. Antel, E. W. Radue, A. de Vera, H. Pohlmann, L. Kappos, and For the FTY720 D2201 Study Group (2009)
Neurology 72, 73-79
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Use of an Exposure-Response Model to Aid Early Drug Development of an Oral Sphingosine 1-Phosphate Receptor Modulator.
S. Rohatagi, H. Zahir, J. B. Moberly, K. E. Truitt, S.-i. Inaba, T. Shimozato, and T. J. Carrothers (2009)
J. Clin. Pharmacol. 49, 50-62
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Deactivation of Sphingosine Kinase 1 by Protein Phosphatase 2A.
R. K. Barr, H. E. Lynn, P. A. B. Moretti, Y. Khew-Goodall, and S. M. Pitson (2008)
J. Biol. Chem. 283, 34994-35002
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