title: Modulating tone: the overture of S1P receptor immunotherapeutics.
abstract: Modulation of complex functions within the immune system has proven to be surprisingly sensitive to alterations in the lysophospholipid sphingosine 1-phosphate (S1P) receptor-ligand rheostat. This has become increasingly evident from both chemical and genetic manipulation of the S1P system, with pharmacological effects upon lymphoid cells, dendritic cell function, as well as vascular interfaces. The integrated immune system, perhaps as a result of its relatively recent evolutionary ontogeny, has selected for a number of critical control points regulated by five distinct high affinity G-protein-coupled receptor subtypes with a shared ligand, with receptors distributed on lymphocytes, dendritic cells, and endothelium. All of these cellular components of the axis are capable of modulating immune responses in vivo, with the impact on the immune response being very different from classical immunosuppressants, by virtue of selective spatial and temporal sparing of humoral and myeloid elements of host defense. Pharmacological subversion of the S1P rheostat is proving to be clinically efficacious in multiple sclerosis, and both the scope and limitations of therapeutic modulation of the S1P axis in immunotherapy are becoming clearer as understanding of the integrated chemical physiology of the S1P system emerges.
authors.affiliation: Department of Chemical Physiology, the Scripps Research Institute, La Jolla, CA 92037, USA. hrosen@scripps.edu
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez-Cabrera
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Stuart
authors.initials: S
authors.lastname: Cahalan
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
authors.forename: M Germana
authors.initials: MG
authors.lastname: Sanna
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004727:Endothelium / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D050356:Lipid Metabolism / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D049349:Receptors, Lysosphingolipid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids