title: Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  Sphingosine-1-phosphate (S1P) regulates the egress of T cells from lymphoid organs; levels of S1P in the tissues are controlled by S1P lyase (Sgpl1). Hence, Sgpl1 offers a target to block T cell-dependent inflammatory processes. However, the involvement of Sgpl1 in models of disease has not been fully elucidated yet, since Sgpl1 KO mice have a short life-span.
  
  
  METHODS
  We generated inducible Sgpl1 KO mice featuring partial reduction of Sgpl1 activity and analyzed them with respect to sphingolipid levels, T-cell distribution, and response in models of inflammation.
  
  
  RESULTS
  The partially Sgpl1 deficient mice are viable but feature profound reduction of peripheral T cells, similar to the constitutive KO mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The therapeutic relevance of Sgpl1 is demonstrated by the fact that the inducible KO mice are protected in experimental autoimmune encephalomyelitis (EAE). T cell immigration into the CNS was found to be profoundly reduced. Since S1P levels in the brain of the animals are unchanged, we conclude that protection in EAE is due to the peripheral effect on T cells, leading to reduced CNS immigration, rather than on local effects in the CNS.
  
  
  CONCLUSIONS
  The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland. andreas.billich@novartis.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
authors.forename: Thomas
authors.initials: T
authors.lastname: Baumruker
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Andrea
authors.initials: A
authors.lastname: Isken
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.forename: Erika
authors.initials: E
authors.lastname: Loetscher
authors.forename: Barbara
authors.initials: B
authors.lastname: Metzler
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuesslein-Hildesheim
authors.forename: Bernadette
authors.initials: B
authors.lastname: Kleylein-Sohn
mesh_terms: D000446:Aldehyde-Lyases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006968:Hypersensitivity, Delayed / Q000097:blood / Q000150:complications / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory / Q000276:immunology; D019426:Integrases / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D012756:Sheep; D013107:Sphingolipids / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D013107:Sphingolipids; C045073:Cre recombinase; D019426:Integrases; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)
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