Development of a Passive Immunization Strategy Against Atherosclerosis
Abstract: Atherosclerosis is a chronic inflammatory disease, characterized by the accumulation of lipids and fibrous tissue in the wall of medium and large-sized arteries. The characteristic culprit of the disease is the atheroma, or atherosclerotic plaque, a patchy thickening of the arterial wall which affects the lumen, inducing various degrees of stenosis. The rupture of the atherosclerotic plaques, followed by local thrombosis, is the underlying cause of myocardial infarction and stroke, which claim millions of lives every year worldwide. Oxidized LDL and the immune system play very important roles in atherosclerosis. Several studies have demonstrated the existence of both atherogenic and atheroprotective immune responses against oxidized LDL. We have identified several of the epitopes in the oxidized LDL particle which trigger immune responses. These epitopes are aldehyde-modified peptide sequences of apoB-100, the main protein in LDL structure. Immunization of atherosclerosis-prone mice with some of the apoB-100 peptides reduced plaque area by up to 60% in the immunized mice compared to controls. We tested the effects of recombinant human IgG1 antibodies against two of these peptide sequences on the development of atherosclerosis in mice. Passive immunization with the IEI-E3 and 2D03 antibodies, specific for MDA-p45 (aa 661-680), significantly inhibited atherosclerosis progression and induced plaque regression in the descending aorta. 2D03 prevented constrictive remodeling after injury in the carotid arteries and potently reduced lesion extent in the uninjured carotid arteries in mice. Additionally, antibody treatment decreased the local and systemic inflammatory responses. We have also found that plasma levels of human IgG1 autoantibodies which recognize the same aldehyde-modified apoB-100 peptide are inversely correlated with carotid stenosis in healthy individuals, which further supports the hypothesis of the potential atheroprotective role of these antibodies. The influence of the antibodies on human atherosclerosis and their potential side effects need to be carefully characterized. In the future, the oxidized LDL-specific recombinant human IgG1 antibodies could be developed into novel diagnostic and therapeutic tools for the management of atherosclerosis-related cardiovascular diseases.
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