OBJECTIVE Oxidized phospholipids (OxPL), such as the oxidized derivatives of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine, and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine, have been shown to be the principal biologically active components of minimally oxidized LDL (low-density lipoprotein). The role of OxPL in cardiovascular diseases is well recognized, including activation of inflammation within vascular cells. Atherosclerotic Apoe-/- mice fed a high-fat diet develop antibodies to OxPL, and hybridoma B-cell lines producing natural anti-OxPL autoantibodies have been successfully generated and characterized. However, as yet, no studies have been reported demonstrating that treatment with OxPL neutralizing antibodies can be used to prevent or reverse advanced atherosclerosis. Approach and Results: Here, using a screening against 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine/1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine, we generated a novel IgM autoantibody, 10C12, from the spleens of Apoe-/- mice fed a long-term Western diet, that demonstrated potent OxPL neutralizing activity in vitro and the ability to inhibit macrophage accumulation within arteries of Apoe-/- mice fed a Western diet for 4 weeks. Of interest, 10C12 failed to inhibit atherosclerosis progression in Apoe-/- mice treated between 18 and 26 weeks of Western diet feeding likely due at least in part to high levels of endogenous anti-OxPL antibodies. However, 10C12 treatment caused a 40% decrease in lipid accumulation within aortas of secreted IgM deficient, sIgM-/-Apoe-/-, mice fed a low-fat diet, when the antibody was administrated between 32-40 weeks of age. CONCLUSIONS Taken together, these results provide direct evidence showing that treatment with a single autoimmune anti-OxPL IgM antibody during advanced disease stages can have an atheroprotective outcome.

中文翻译：

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新型自身免疫 IgM 抗体可减轻 IgM 缺乏的低脂饮食喂养小鼠的动脉粥样硬化，但不能减轻西方饮食喂养的 Apoe-/- 小鼠。

目的 氧化磷脂 (OxPL)，例如 1-棕榈酰-2-花生四烯酰-sn-甘油-3-磷酰胆碱、1-棕榈酰-2-(5-氧代戊酰)-sn-甘油-3-磷酰胆碱的氧化衍生物，以及1-棕榈酰-2-戊二酰-sn-甘油-3-磷酸胆碱已被证明是最低限度氧化的 LDL（低密度脂蛋白）的主要生物活性成分。OxPL 在心血管疾病中的作用已得到广泛认可，包括激活血管细胞内的炎症。饲喂高脂肪饮食的动脉粥样硬化 Apoe-/- 小鼠会产生 OxPL 抗体，并且已成功生成并表征了产生天然抗 OxPL 自身抗体的杂交瘤 B 细胞系。然而，迄今为止，尚无研究报道证明 OxPL 中和抗体治疗可用于预防或逆转晚期动脉粥样硬化。方法和结果：在这里，通过针对 1-棕榈酰-2-(5-氧代戊酰)-sn-甘油-3-磷酸胆碱/1-棕榈酰-2-戊二酰-sn-甘油-3-磷酸胆碱的筛选，我们生成了一种新的IgM 自身抗体 10C12，来自长期喂养西方饮食的 Apoe-/- 小鼠的脾脏，该抗体在体外表现出有效的 OxPL 中和活性，并且能够抑制长期喂养西方饮食的 Apoe-/- 小鼠动脉内巨噬细胞积聚。 4周。有趣的是，10C12 未能抑制接受西方饮食喂养 18 至 26 周的 Apoe-/- 小鼠的动脉粥样硬化进展，这可能至少部分归因于高水平的内源性抗 OxPL 抗体。然而，当在 32-40 周龄之间施用抗体时，10C12 治疗导致分泌性 IgM 缺陷、sIgM-/-Apoe-/-、喂食低脂饮食的小鼠主动脉内脂质积累减少 40%。结论 总而言之，这些结果提供了直接证据，表明在疾病晚期阶段使用单一自身免疫抗 OxPL IgM 抗体治疗可以产生动脉粥样硬化结果。