Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
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.
Mandala
Suzanne
S
Department of Immunology and Rheumatology, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA.
Hajdu
Richard
R
Bergstrom
James
J
Quackenbush
Elizabeth
E
Xie
Jenny
J
Milligan
James
J
Thornton
Rosemary
R
Shei
Gan-Ju
GJ
Card
Deborah
D
Keohane
CarolAnn
C
Rosenbach
Mark
M
Hale
Jeffrey
J
Lynch
Christopher L
CL
Rupprecht
Kathleen
K
Parsons
William
W
Rosen
Hugh
H
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*
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