Regulatory T-Cell Response to Apolipoprotein B100-Derived Peptides Reduces the Development and Progression of Atherosclerosis in Mice

Objective-The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance. Methods and Results-Young or old Apoe(-/-) mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)-derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young Apoe(-/-) mice (P=0.001 versus OVA group) and abrogated atherosclerosis progression in old Apoe(-/-) mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group, P<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alter antibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1-related and T helper type 2-related cytokines. Interestingly, depletion of CD4(+)CD25(+) Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection. Conclusion-Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to Apoe(-/-) mice reduces atherosclerosis through the induction of a specific Treg cell response. (Arterioscler Thromb Vasc Biol. 2012;32:605-612.)