Department of Cardiovascular, Respiratory, and Metabolic Medicine, Kagoshima University, Kagoshima, Japan (Y.F., M.M., Y.A., N.H., T. Miyauchi, Y.I., T.S., K.I., C.T.).
J Am Heart Assoc. 2012 Aug;1(4):e003079. doi: 10.1161/JAHA.112.003079. Epub 2012 Aug 24.
Folate receptor β (FRβ) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated Pseudomonas exotoxin A (PE38) conjugated to an anti-FRβ antibody (anti-FRβ-PE38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting FRβ on atherosclerosis, we determined the presence of FRβ-expressing macrophages in atherosclerotic lesions and administered the FRβ immunotoxin in apolipoprotein E-deficient mice.
The FRβ-expressing macrophages were observed in atherosclerotic lesions of apolipoprotein E-deficient mice. At 15 or 35 weeks of age, the apolipoprotein E-deficient mice were divided into 3 groups and were intravenously administered 0.1 mg/kg of anti-FRβ-PE38 (immunotoxin group), 0.1 mg/kg of PE38 (toxin group), or 0.1 mL of saline (control group) every 3 days, for a total of 5 times for each age group. The mice were analyzed at 21 or 41 weeks of age. Treatment with the immunotoxin resulted in 31% and 22% reductions in atherosclerotic lesions of the 21- and 41-week-old mice, respectively (P<0.05). Administration of immunotoxin reduced the numbers of FRβ- and tumor necrosis factor-α-expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (P<0.05). Real-time polymerase chain reaction demonstrated that the expression of FRβ and tumor necrosis factor-α mRNA was significantly decreased in the immunotoxin group (P<0.05).
These results suggest that FRβ-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E-deficient mice and that FRβ immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant FRβ immunotoxin targeting activated macrophages could provide a novel therapeutic tool for atherosclerosis. (J Am Heart Assoc. 2012;1:e003079 doi: 10.1161/JAHA.112.003079.).
叶酸受体β（FRβ）在巨噬细胞激活时被诱导。一种由截短的绿脓杆菌外毒素 A（PE38）与抗 FRβ 抗体（抗 FRβ-PE38）偶联而成的重组免疫毒素已被报道可杀伤炎症疾病中的激活巨噬细胞。为了阐明针对 FRβ 的免疫毒素对动脉粥样硬化的影响，我们在动脉粥样硬化病变中确定了表达 FRβ 的巨噬细胞的存在，并在载脂蛋白 E 缺陷小鼠中给予 FRβ 免疫毒素。
在载脂蛋白 E 缺陷小鼠的动脉粥样硬化病变中观察到表达 FRβ 的巨噬细胞。在 15 或 35 周龄时，将载脂蛋白 E 缺陷小鼠分为 3 组，分别静脉注射 0.1mg/kg 的抗 FRβ-PE38（免疫毒素组）、0.1mg/kg 的 PE38（毒素组）或 0.1ml 的生理盐水（对照组），每 3 天一次，每个年龄组共给药 5 次。在 21 或 41 周龄时对小鼠进行分析。免疫毒素治疗使 21 周和 41 周龄小鼠的动脉粥样硬化病变分别减少了 31%和 22%（P<0.05）。免疫毒素给药减少了 FRβ 和肿瘤坏死因子-α 表达的巨噬细胞数量，减少了细胞增殖，并增加了凋亡细胞的数量（P<0.05）。实时聚合酶链反应显示免疫毒素组 FRβ 和肿瘤坏死因子-α mRNA 的表达显著降低（P<0.05）。
这些结果表明，载脂蛋白 E 缺陷小鼠的动脉粥样硬化病变中存在表达 FRβ 的巨噬细胞，FRβ 免疫毒素给药可减少年轻和年老个体中动脉粥样硬化病变的进展。针对激活的巨噬细胞的重组 FRβ 免疫毒素可能为动脉粥样硬化提供一种新的治疗工具。（J Am Heart Assoc. 2012;1:e003079 doi: 10.1161/JAHA.112.003079.）。
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