Induction of Anti-Anti-Idiotype Antibodies Against Sulfated Glycosaminoglycans Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 12; pp. 2847 - 2854
• Main Authors: Brito, Víctor, Mellal, Katia, Portelance, Simon Giroux, Pérez, Arlenis, Soto, Yosdel, deBlois, Denis, Ong, Huy, Marleau, Sylvie, Vázquez, Ana María
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2012; Lippincott Williams & Wilkins
• Subjects: Animals; Antibodies, Anti-Idiotypic - immunology; Antibodies, Anti-Idiotypic - therapeutic use; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Arteries - metabolism; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol, Dietary - adverse effects; Diabetes. Impaired glucose tolerance; Diet, High-Fat - adverse effects; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Glycosaminoglycans - immunology; Glycosaminoglycans - metabolism; Humans; Lipoproteins, LDL - metabolism; Male; Medical sciences; Mice; Mice, Knockout; Mutant Chimeric Proteins - immunology; Mutant Chimeric Proteins - therapeutic use; Sulfates - metabolism; glycosaminoglycans; Rodentia; Cardiovascular disease; anti-idiotype; Vascular disease; Vertebrata; Mammalia; Treatment; Mouse; Apolipoprotein E; Animal; Immunotherapy; Atherosclerosis; Glycosaminoglycan; antibodies
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.300444

OBJECTIVE—The pathogenesis of atherosclerosis is associated with the early retention of low-density lipoproteins that are trapped in the extracellular matrix of the arterial intima by interaction with glycosaminoglycan side chains of proteoglycans. Mutant mouse/human chimeric antibodies of the murine monoclonal antibody P3, which react with N-glycolyl–containing gangliosides and sulfated glycosaminoglycans, were tested for their potentially antiatherogenic properties through the induction of an idiotypic antibody network that may specifically interfere with the binding of low-density lipoproteins to proteoglycan side chains, low-density lipoprotein modification, and foam cell formation. METHODS AND RESULTS—Apolipoprotein E–deficient mice fed a high-fat, high-cholesterol diet received 5 to 6 doses of chP3R99 or chP3S98 mutant antibodies, showing high and low reactivity, respectively, against their respective antigens. Both chimeric antibodies elicited an immunodominant anti-idiotypic response in the absence of adjuvant. A striking (40%–43%) reduction (P<0.01) in total lesion areas was observed in 18-week-old mice immunized with chP3R99, but not chP3S98, compared with PBS-treated mice. The antiatherosclerotic effect was associated with increased mice sera reactivity against heparin and sulfated glycosaminoglycans, including chondroitin and dermatan sulfate. In addition, purified IgG from chP3R99-immunized mice blocked the retention of apolipoprotein B–containing lipoproteins within the arterial wall of apolipoprotein E mice. CONCLUSION—The present study supports use of active immunization and the mounting of an idiotypic antibody network response against glycosaminoglycans as a novel approach to target atherosclerosis.