Abstract 756: Continuous Subcutaneous Delivery Of Apolipoprotein B-derived Peptides Induces T Cells Anergy And Reduces The Progression Of Established Atherosclerosis In Mice
Atherosclerosis is a chronic inflammatory disease of the arterial wall promoted by both innate and adaptive Th1-driven immunity. Recent studies identified a number of native and MDA-modified peptide sequences in apoB-100 that induce immune responses in humans and reduce atherosclerosis in mice when administered with adjuvant. An alternative way of modulating the immune response involves continuous subcutaneous infusion of low doses of antigen without adjuvant, which lead to the induction of a state of immune tolerance with significant dampening of pathogenic T cell responses. We investigated this modulatory treatment in Apoe−/ − mice using a set of apoB-100 peptides identified as the most immunoreactive in patients suffering of coronary disease. Using subcutaneous osmotic pump, 36 weeks old Apoe−/ − mice received infusion of a mixture of 3 apoB100 peptides (P210, MDA-P210 and P240) at a dose of 10 μg/day, during 14 or 28 days. A control group was infused with an OVA peptide at a similar dose for 14 days. The mice were sacrified at 46 weeks of age (6 or 8 weeks after the end of the treatment period) and were used for analysis of atherosclerotic lesion size and immulological studies using isolated spleen-derived T and dendritic cells. Treatment with apoB100 peptides induced a significant decrease of lesion size in aortic sinus (766 125±49 768 μm2 and 777 567±31 749 μm2) compared to OVA-treated mice (920 556±33 240 μm2, P=0.02 and P=0.007, respectively). This effect was observed despite similar total cholesterol level in the three groups. Treatment with apoB peptides abrogated lesion progression compared to baseline values at 36 weeks of age (783 076±82 292 μm2), whereas lesions of OVA-treated mice showed significant progression (P= 0.02 vs baseline). CD3-stimulated splenic T cells isolated from peptides-treated mice produced lower levels of IFNg (1450±279 vs 4417±218 pg/ml; P<0.001) and IL10 (30.2±19.9 vs 505±9.5 pg/ml; P<0.001) than CD4+ T cells from OVA-treated mice. These results suggest that continuous subcutaneous delivery of apoB-derived peptides without adjuvant induces T cell anergy and reduces atherosclerosis progression. Further studies are required to examine the role of natural or adaptive regulatory T cells in this process.