Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis.
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.
van Puijvelde
G H M
GH
Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands. puijvelde@lacdr.leidenuniv.nl
Hauer
A D
AD
de Vos
P
P
van den Heuvel
R
R
van Herwijnen
M J C
MJ
van der Zee
R
R
van Eden
W
W
van Berkel
T J C
TJ
Kuiper
J
J
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*
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