Division of Immunobiology, Center of Molecular Immunology, 216 St and 15th Ave, Siboney, Playa PO Box 16040, Havana 11600, Cuba.
Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2847-54. doi: 10.1161/ATVBAHA.112.300444. Epub 2012 Oct 18.
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.
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.
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.
动脉粥样硬化的发病机制与低密度脂蛋白（LDL）的早期滞留有关，这些 LDL 通过与蛋白聚糖的糖胺聚糖侧链相互作用而滞留在动脉内膜的细胞外基质中。通过诱导可能特异性干扰 LDL 与蛋白聚糖侧链结合、LDL 修饰和泡沫细胞形成的独特型抗体网络，测试了反应性 N-羟乙酰神经氨酸糖脂和硫酸化糖胺聚糖的鼠单克隆抗体 P3 的突变体鼠/人嵌合抗体的潜在抗动脉粥样硬化特性。
喂食高脂肪、高胆固醇饮食的载脂蛋白 E 缺陷型小鼠接受了 5 至 6 次 chP3R99 或 chP3S98 突变体抗体的注射，这两种抗体分别对其相应抗原具有高和低的反应性。在没有佐剂的情况下，两种嵌合抗体都引发了免疫优势的抗独特型反应。与 PBS 处理的小鼠相比，用 chP3R99 免疫的 18 周龄小鼠的总病变面积显著减少（40%-43%，P<0.01），但 chP3S98 则没有。抗动脉粥样硬化作用与增加的小鼠血清对肝素和硫酸化糖胺聚糖（包括软骨素和硫酸皮肤素）的反应性有关。此外，从 chP3R99 免疫的小鼠中纯化的 IgG 阻断了载脂蛋白 B 载脂蛋白 E（-/-）小鼠动脉壁内脂蛋白的滞留。
本研究支持使用主动免疫和针对糖胺聚糖的独特型抗体网络反应作为靶向动脉粥样硬化的新方法。
