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(Circulation. 2006;114:1968-1976.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Induction of Oral Tolerance to Oxidized Low-Density Lipoprotein Ameliorates Atherosclerosis

G.H.M. van Puijvelde, MSc; A.D. Hauer, PhD; P. de Vos, BSc; R. van den Heuvel, BSc; M.J.C. van Herwijnen, BSc; R. van der Zee, PhD; W. van Eden, PhD; T.J.C. van Berkel, PhD; J. Kuiper, PhD

From the Division of Biopharmaceutics, Leiden University, Leiden (G.H.M.v.P., A.D.H., P.d.V., R.v.d.H., M.J.C.v.H., T.J.C.v.B., J.K.), and Department of Infectious Diseases and Immunology, Utrecht University, Utrecht (R.v.d.Z., W.v.E.), Netherlands.

Correspondence to G.H.M. van Puijvelde, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, PO Box 9502, 2300 RA Leiden, Netherlands. E-mail puijvelde{at}lacdr.leidenuniv.nl

Received February 16, 2006; revision received June 23, 2006; accepted July 28, 2006.

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.

Methods and 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-ß 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.

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