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. 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-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(+)D25(+)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.