Immunization with cholesterol-rich liposomes induces anti-cholesterol antibodies and reduces diet-induced hypercholesterolemia and plaque formation

• Published in: The Journal of laboratory and clinical medicine 1996, Vol.127 (1), p.40-49
• Main Authors: Alving, Carl R., Swartz, Glenn M., Wassef, Nabila M., Ribas, Jorge L., Herderick, Edward E., Virmani, Renu, Kolodgie, Frank D., Matyas, Gary R., Cornhill, J.Fredrick
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - immunology; Antibody Formation; Arteriosclerosis - immunology; Arteriosclerosis - pathology; Arteriosclerosis - prevention & control; Biological and medical sciences; Cholesterol - administration & dosage; Cholesterol - blood; Cholesterol - immunology; Cholesterol, Dietary - adverse effects; Disorders of blood lipids. Hyperlipoproteinemia; Drug Carriers; Hypercholesterolemia - etiology; Hypercholesterolemia - pathology; Hypercholesterolemia - therapy; Immunization; Lipoproteins - immunology; Lipoproteins, IDL; Lipoproteins, VLDL - immunology; Liposomes; Medical sciences; Metabolic diseases; Rabbits
• ISSN: 0022-2143; 1532-6543
• DOI: 10.1016/S0022-2143(96)90164-X

Immunization of rabbits with a protein-free formulation consisting of liposomes containing 71% cholesterol and lipid A as an adjuvant induced anticholesterol antibodies that caused complement-dependent lysis of liposomes lacking lipid A. The antibodies, immunoglobulin G (IgG) and immunoglobulin M (IgM), also recognized nonoxidized crystalline cholesterol as an antigen by enzyme-linked immunosorbent assay (ELISA). The effects of immunization against cholesterol on elevations in serum cholesterol and development of atherosclerosis were examined in rabbits fed a diet containing 0.5% to 1.0% cholesterol. Although the mean serum cholesterol level, mainly in the form of very-low-density lipoprotein cholesterol, rose as much as 60-fold in the nonimmunized rabbits, the elevation was significantly less—as much as 35% lower—in the immunized rabbits. Elevation of serum cholesterol was accompanied by an apparent drop in the level of antibodies on initiating the diet, followed by a rebound on stopping the diet, thus suggesting that the antibodies were adsorbed to cholesterol that was present in circulating lipoproteins. When lipoprotein fractions—composed of either very-low-density and intermediate-density lipoproteins derived from cholesterol-fed nonimmunized rabbits or human low-density lipoproteins—were tested as capture antigens by solid-phase ELISA, reactivity was observed with IgG and IgM antibodies present in the serum of immunized rabbits. Immunization also resulted in a marked decrease in the risk of developing atherosclerosis. Analysis of aortic atherosclerosis by quantitative histologic examination and fatty streaks by automated morphometric probability-of-occurrence mapping showed diminished atherosclerosis in most areas of the aorta in vaccine recipients. It is proposed that immunization with liposomes containing 71% cholesterol and lipid A can reduce diet-induced hypercholesterolemia and atherosclerosis.