Modulating Autoimmunity against LDL: Development of a Vaccine against Atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the arterial wall that leads to the build-up of occluding atherosclerotic plaques. Its clinical sequelae, myocardial infarction and stroke, represent the most frequent causes of death worldwide. Atherosclerosis is a multifactorial pathology that involves traditional risk factors and chronic low-grade inflammation in the atherosclerotic plaque and systemically. This process is accompanied by a strong autoimmune response that involves autoreactive T cells in lymph nodes and atherosclerotic plaques, as well as autoantibodies that recognize low-density lipoprotein (LDL) and its main protein component apolipoprotein B (ApoB). In the past 60 years, numerous preclinical observations have suggested that immunomodulatory vaccination with LDL, ApoB, or its peptides has the potential to specifically dampen autoimmunity, enhance tolerance to atherosclerosis-specific antigens, and protect from experimental atherosclerosis in mouse models. Here, we summarize and discuss mechanisms, challenges, and therapeutic opportunities of immunomodulatory vaccination and other strategies to enhance protective immunity in atherosclerosis.

Effect of Aspirin on Experimental Atherosclerosis in Rabbits Submitted to Hypercholesterolemic Diet

Aspirin, besides its antithrombotic activity, has also been quoted for protective effect reducing new coronary lesions. Objective: Considering the growing interest in the study of drugs that prevent the progression of atherosclerotic lesion, the objective of this study was to determine the effect of aspirin in experimental atherogenesis induced in rabbits fed with cholesterol rich diets. Method: Thirty adult, New Zealand white male rabbits, with 3.4 kg of body weight were submitted to a 1.5% cholesterol-rich-diet for 9 weeks. Aspirin was triturated, mixed with chloroform and incorporated to the normal chow. The drug was given to the rabbits every day in portions of 20 g of chow with 100 mg of aspirin. The rabbits were divided in 3 groups as follows: A) Cholesterol-rich-diet (n=10); B) Cholesterol-rich-diet plus aspirin (n=10) and C) Normal chow (n=10). Blood samples were collected before starting the diet, at 5 weeks and at sacrifice (9 weeks) for determination of total cholesterol, triglycerides, enzymes and hematological tests. After sacrifice, staining of the aorta was done by Sudan III for visualization of sudanophillic plaques. The percentual of aorta couvered with lipidic deposits were determined by computerized planimetry. Results: Total cholesterol (mg/dl) was per group: A- TO=52, T5=424 and T9=1.483; B- TO=32, T5=755 and T9=1.436; C- TO=41, T5=22 and T9=27. Planimetry data did not differ among groups A (23.3%) and B (27.3%). Scanning microscopy – the interpretation of the document images in three groups showed insignificant platelet deposition in all aortic segments both in groups B and C. Conclusion: This experiment enhances the theoretic basis for the protective effect of aspirin as an antiaggregant factor in the experimental aortic atherosclerotic lesion.

Auto-Antibody Production During Experimental Atherosclerosis in ApoE-/- Mice

Current models stipulate that B cells and antibodies function during atherosclerosis in two distinct ways based on antibody isotype, where IgM is protective and IgG is inflammatory. To examine this model, we generated ApoE-/- Aid-/- mice, which are unable to produce IgG antibodies due to the absence of activation-induced deaminase (AID) but maintain high plasma cholesterol due to the absence of apolipoprotein E (APOE). We saw a dramatic decrease in plaque formation in ApoE-/- Aid-/- mice compared to ApoE-/- mice. Rigorous analysis of serum antibodies revealed both ApoE-/- and ApoE-/- Aid-/- mice had substantially elevated titers of IgM antibodies compared to C57BL/6J controls, suggesting a more complex dynamic than previously described. Analysis of antigen specificity demonstrated that ApoE-/- Aid-/- mice had elevated titers of antibodies specific to malondialdehyde-oxidized low density lipoprotein (MDA-oxLDL), which has been shown to block macrophage recruitment into plaques. Conversely, ApoE-/- mice showed low levels of MDA-oxLDL specificity, but had antibodies specific to numerous self-proteins. We provide evidence for a hierarchical order of antibody specificity, where elevated levels of MDA-oxLDL specific IgM antibodies inhibit plaque formation. If the level of MDA-oxLDL specific IgM is insufficient, self-reactive IgM and IgG antibodies are generated against debris within the arterial plaque, resulting in increased inflammation and further plaque expansion.

Effects of Hamo NK hard capsule on experimental atherosclerosis model

This study evaluated the effects of Hamo NK hard capsule on athresclerosis using experimental atherosclerosis model. NewZealand White rabbits were fed a high-fat diet (HFD) containing cholesterol and peanut oil. The animals received oral administration of HFD and Hamo NK hard capsule at two doses of 0.126 and 0.378 g/kg bw/day for 8 consecutive weeks. Blood samples were collected for analyis of biochemical parameters at before treatment, week 4 and week 8. Histopathology assessments of the aortic artery and liver were carried out at the end of the experiment. Hamo NK was effective in reducing serum triglyceride level after 8 weeks of the experiment. In addition, Hamo NK at two doses of 0.126 g/kg b.w and 0.378 g/kg b.w for 8 consecutive weeks did not affect the cholesterol, LDL-C and HDL-C concentrations induced by a HFD. Hamo NK at the dose of 0.126 g/kg bw/day was not only able to decrease significant aortic surface lesions but also capable of managing atherosclerosis plaques formation in aorta; whereas theses activities were not notiaceable at the dose of 0.378 g/kg b.w.