Induction of Anti-Anti-Idiotype Antibodies Against Sulfated Glycosaminoglycans Reduces Atherosclerosis in Apo lipoprotein E-Deficient Mice

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 proteog,lycan 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 Ig,G 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. (Arterioscler Thromb Vasc Biol. 2012;32:2847-2854.)