title: Sphingosine-1-phosphate analogue FTY720 causes lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice.
abstract: OBJECTIVE
  Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.
  
  
  RESULTS
  ApoE-/- mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+ CD44hi CD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.
  
  
  CONCLUSIONS
  FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.
authors.affiliation: Department of Cardiology, University Hospital Heidelberg, Germany. roland.klingenberg@ki.se
authors.forename: Roland
authors.initials: R
authors.lastname: Klingenberg
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
authors.forename: Erwin
authors.initials: E
authors.lastname: Blessing
authors.forename: Michael
authors.initials: M
authors.lastname: Preusch
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Grone
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Dengler
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000276:immunology / Q000503:physiopathology; D000068876:Fingolimod Hydrochloride; D006937:Hypercholesterolemia / Q000139:chemically induced*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects; D008214:Lymphocytes / Q000097:blood / Q000187:drug effects; D008231:Lymphopenia / Q000139:chemically induced; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine