Abstract 1352: Immunomodulation with OCH-Primed Dendritic Cells Ameliorates Atherosclerosis
OCH is a low molecular weight synthetic lipid that specifically activates natural killer T (NKT) cells, resulting in rapid production of large amounts of Th2 cytokines. Recent studies show that in vivo administration of OCH results in suppression of Th1 mediated immune responses in autoimmune diseases. NKT cell activation depends on lipid presentation via the MHC-II like molecule CD1d on antigen presenting cells such as mature dendritic cells (mDCs). The goal of this study was to investigate the effect of OCH and OCH-primed dendritic cells on atherogenesis. LDL receptor deficient (LDLr−/−) mice were fed a Western type diet and atherosclerosis was induced via collar placement around both carotid arteries. Subsequently the mice were treated i.p. with OCH (N=13) or PBS (N=11) twice a week for seven weeks. The injections with OCH did not significantly affect the atherosclerotic lesion size. To improve the presentation of OCH to NKT cells in vivo, bone marrow-dendritic cells were maturated via TLR4 activation, in the presence or absence of OCH. Subsequently we transferred 1.5x106 mDCs (N=11) or OCH-primed mDCs (N=11) (3 times, every other day) to LDLr−/− mice. Control mice received PBS (N=8). Afterwards the mice were put on a Western type diet to induce atherosclerosis. Vaccination with OCH-primed DCs resulted in a 70.6% and 80.7% reduction in plaque size compared to mice treated with mDCs or PBS (9.400±2.185 μm2 vs. 31.920±7.914 μm2 and 48.578±9.231 μm2, p<0.05), respectively. During the experiment no effect on initial total serum cholesterol levels was observed, although at the end of the experiment there was a significant 23.7% (p<0.05) reduction in cholesterol levels in the mice treated with OCH-primed DCs compared to the group treated with mDCs. The amount of CD3+NK1.1+ cells in blood was monitored and a 5.2-fold increase in these NKT cells was detected 3 days after the last treatment with OCH-primed DCs compared to mDC treatment (2.1±0.4% vs. 0.4±0.1%, p<0.05). We conclude that immunotherapy using OCH-primed dendritic cells efficiently activates NKT cells, resulting in a Th2 phenotype and leading to an efficient protection against atherosclerosis. These data indicate that immunotherapy based on ligand specific primed DCs may be a novel way to treat atherosclerosis.