Objective-HSP60-specific T cells contribute to the development of the immune responses in atherosclerosis. This can be dampened by regulatory T cells activated via oral tolerance induction, and we explored the effect of oral tolerance induction to HSP60 and the peptide HSP60 (253 to 268) on atherosclerosis. Methods and Results-HSP60 and HSP60 (253 to 268) were administered orally to LDLr Ϫ/Ϫ mice before induction of atherosclerosis and resulted in a significant 80% reduction in plaque size in the carotid arteries and in a 27% reduction in plaque size at the aortic root. Reduction in plaque size correlated with an increase in CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells in several organs and in an increased expression of Foxp3, CD25, and CTLA-4 in atherosclerotic lesions of HSP60-treated mice. The production of interleukin (IL)-10 and transforming growth factor (TGF)-␤ by lymph node cells in response to HSP60 was observed after tolerance induction. Conclusion-Oral tolerance induction to HSP60 and a small HSP60-peptide leads to an increase in the number of CD4 ϩ CD25 ϩ Foxp3 ϩ regulatory T cells, resulting in a decrease in plaque size as a consequence of increased production of IL-10 and TGF-␤. We conclude that these beneficial results of oral tolerance induction to HSP60 and HSP60 (253 to 268) may provide new therapeutic approaches for the treatment of atherosclerosis. (Arterioscler Thromb Vasc Biol.

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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 Ϫ/Ϫ 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%; PϽ0.05) and progression (45%; PϽ0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4 ϩ CD25 ϩ Foxp3