title: Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis.
abstract: BACKGROUND
  Oxidation of low-density lipoprotein (LDL) and the subsequent processing of oxidized LDL (oxLDL) by macrophages results in activation of specific T cells, which contributes to the development of atherosclerosis. Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis.
  
  
  RESULTS
  Tolerance to oxLDL and malondialdehyde-treated LDL (MDA-LDL) was induced in LDL receptor-/- mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis. Oral tolerance to oxLDL resulted in a significant attenuation of the initiation (30% to 71%; P<0.05) and progression (45%; P<0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4+ CD25+ Foxp3+ cells in spleen and mesenteric lymph nodes, and these cells specifically responded to oxLDL with increased transforming growth factor-beta production. Tolerance to oxLDL also increased the mRNA expression of Foxp3, CTLA-4, and CD25 in the plaque. In contrast, tolerance to MDA-LDL did not affect atherogenesis.
  
  
  CONCLUSIONS
  OxLDL-specific T cells, present in LDL receptor-/- mice and important contributors in the immune response leading to atherosclerotic plaque, can be counteracted by oxLDL-specific CD4+ CD25+ Foxp3+ regulatory T cells activated via oral tolerance induction to oxLDL. We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis.
authors.affiliation: Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands. puijvelde@lacdr.leidenuniv.nl
authors.forename: G H M
authors.initials: GH
authors.lastname: van Puijvelde
authors.forename: A D
authors.initials: AD
authors.lastname: Hauer
authors.forename: P
authors.initials: P
authors.lastname: de Vos
authors.forename: R
authors.initials: R
authors.lastname: van den Heuvel
authors.forename: M J C
authors.initials: MJ
authors.lastname: van Herwijnen
authors.forename: R
authors.initials: R
authors.lastname: van der Zee
authors.forename: W
authors.initials: W
authors.lastname: van Eden
authors.forename: T J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: J
authors.initials: J
authors.lastname: Kuiper
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000378:metabolism; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C502964:malondialdehyde-low density lipoprotein, mouse; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde