title: 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.
authors.affiliation: Department of Immunology and Rheumatology, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mandala
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.forename: James
authors.initials: J
authors.lastname: Bergstrom
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Quackenbush
authors.forename: Jenny
authors.initials: J
authors.lastname: Xie
authors.forename: James
authors.initials: J
authors.lastname: Milligan
authors.forename: Rosemary
authors.initials: R
authors.lastname: Thornton
authors.forename: Gan-Ju
authors.initials: GJ
authors.lastname: Shei
authors.forename: Deborah
authors.initials: D
authors.lastname: Card
authors.forename: CarolAnn
authors.initials: C
authors.lastname: Keohane
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenbach
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hale
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
authors.forename: Kathleen
authors.initials: K
authors.lastname: Rupprecht
authors.forename: William
authors.initials: W
authors.lastname: Parsons
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D001667:Binding, Competitive; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000139:chemically induced; D008246:Lysophospholipids; D051379:Mice; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D011409:Propylene Glycols / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*
chemical_list: C453461:2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butyl phosphate; C453462:3-amino-3-(hydroxymethyl)-5-(4-octylphenyl)pentanephosphonic acid; D007166:Immunosuppressive Agents; D008024:Ligands; D008246:Lysophospholipids; D010755:Organophosphates; D063065:Organophosphonates; D011409:Propylene Glycols; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; C060506:sphingosine 1-phosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium