Abstract 1350: OxLDL-Pulsed Dendritic Cells: An Immunotherapy in Atherosclerosis
Modification of lipoproteins plays an important role in the development of atherosclerosis. Oxidatively modified LDL (oxLDL) has a number of pro-inflammatory effects, whereas immunization with various forms of oxLDL is able to reduce atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatory effects of modified LDL. In this study we transferred oxLDL-pulsed dendritic cells (DCs) to LDLr−/− mice and examined the effects of these cells on atherosclerosis. Bone marrow derived DCs (DCs) were cultured for 10 days in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF). Immature DCs were pulsed with cupper oxidized LDL (Cu-oxLDL) and further matured by TLR4 activation. LDLr−/− mice were injected (3 times, every other day) with 1.5 x106 mature DCs (n=11), oxLDL-pulsed mature DCs (n=11) or were treated with saline (n=8) before induction of atherosclerosis by Western type diet feeding and subsequent perivascular collar placement. Mice were sacrificed 8 weeks after collar placement. Transfer of oxLDL-pulsed DCs resulted in a 91.7 % and 87.5 % reduction in carotid artery lesion size and 87.4% and 84.7 % reduction of intima/lumen ratio compared to the PBS-treated or mature DCs-treated groups, respectively (p<0.01). The reduction in atherosclerosis was accompanied by a 3.8 fold increase (p<0.05) in Cu-oxLDL specific IgG titers in mice treated with oxLDL-pulsed DCs, whereas the levels of anti-MDA-LDL IgG and IgM were not significantly affected. Initially, treatment with oxLDL-pulsed DCs did not affect serum cholesterol levels up to 3 weeks of diet. However, after 10 weeks of diet there was a significant 23.7% reduction in serum cholesterol levels compared to the groups treated with mDCs (p<0.05). We conclude that oxLDL-pulsed DCs induce the proliferation of memory cells which are responsible for the enhanced production of anti-oxLDL IgG. Due to these higer titers, the immunostimulatory effects of oxLDL on the arterial wall are inhibited as shown by the highly significant reduction in lesion size. These data indicate that vaccination with oxLDL-pulsed DCs provides a novel and powerful strategy in the treatment of atherosclerosis.