A Novel Monoclonal Antibody for RAGE-Directed Imaging Identifies Accelerated Atherosclerosis in Diabetes
A Novel Monoclonal Antibody for RAGE-Directed Imaging Identifies Accelerated Atherosclerosis in Diabetes
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DOI：
10.2967/jnumed.109.064659
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发表时间：
2010-01-01
影响因子：
9.3
通讯作者：
Johnson, Lynne L.
中科院分区：
文献类型：
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作者：
Tekabe, Yared;Luma, Joane;Johnson, Lynne L.
晚期糖基化终产物受体(RAGE)结合晚期糖基化终末产物和其他炎症配体，在糖尿病和非糖尿病受试者的动脉粥样硬化斑块中表达。糖尿病患者的高表达与动脉粥样硬化进程加快相对应。这项研究旨在验证这样一种假设，即动脉粥样硬化中RAGE的表达水平可以通过体内定量SPECT来检测，并且靶细胞的计数将与生物信号的强度相关。方法：制备抗RAGE V结构域的单抗，经F(ab‘)(2)片段标记~(99m)Tc，以15.14+/-1.23MBq的剂量注射于24周龄雄性载脂蛋白E缺失(ApoE(-/-))小鼠(n=22)，包括链脲佐菌素诱导的糖尿病小鼠(n=8)、非糖尿病小鼠(n=8)和对照ApoE(-/-)/RAGE(-/-)双基因敲除小鼠(n=6)。四小时后(允许清除血池)，对小鼠进行成像并处死，取下近端主动脉并计数以计算每克组织注射RAGE的百分比，然后进行组织学和免疫组织化学鉴定。结果：SPECT无创、清晰地显示了主动脉病变的放射性示踪剂摄取。糖尿病载脂蛋白E(-/-)组RAGE摄取百分率(1.39+/-0.16x10(-2))显著高于非糖尿病载脂蛋白E(-/-)组(0.48+/-0.27x10(-2))(P<；0.0001)。放射性示踪剂摄取与免疫组织形态计量学的RAGE表达及巨噬细胞百分率高度相关(r=0.86P<；0.0001)。结论：在本研究中，(99m)Tc标记的抗RAGE F(ab‘)(2)SPECT成功地识别了年龄匹配的ApoE(-/-)小鼠的糖尿病早期加速病变，并对一系列病变严重程度的RAGE表达进行了定量。
Receptor for advanced glycation end products (RAGE) binds advanced glycation end products and other inflammatory ligands and is expressed in atherosclerotic plaques in diabetic and nondiabetic subjects. The higher expression in diabetes mellitus corresponds to the accelerated course of the atherosclerosis. This study was designed to test the hypothesis that the level of RAGE expression in atherosclerosis can be detected by quantitative in vivo SPECT and that counts in the target will correlate with the strength of the biologic signal. Methods: A monoclonal murine antibody was developed against the V-domain of RAGE, fragmented into F(ab')(2) and labeled with (99m)Tc, and injected at a dose of 15.14 +/- 1.23 MBq into 24-wk-old male apolipoprotein E null (ApoE(-/-)) mice (n = 22), including mice with streptozotocin-induced diabetes mellitus (n = 8), nondiabetic mice (n = 8), and control ApoE(-/-)/RAGE(-/-) double-knock-out mice (n = 6). Four hours later ( allowing for blood-pool clearance), the mice were imaged and sacrificed, and the proximal aorta was removed and counted to calculate the percentage injected dose of RAGE per gram of tissue, followed by histologic and immunohistochemical characterization. Results: Radiotracer uptake in the aortic lesions was clearly visualized noninvasively by SPECT. RAGE uptake as percentage injected dose in diabetic ApoE(-/-) mice (1.39 +/- 0.16 x 10(-2)) was significantly higher than that in nondiabetic ApoE(-/-) mice (0.48 +/- 0.27 x 10(-2)) (P < 0.0001). The radiotracer uptake was highly correlated with RAGE expression by quantitative immunohistomorphometry (r = 0.82, P = 0.002) and with percentage of macrophages (r = 0.86, P < 0.0001). Conclusion: In this study, (99m)Tc-labeled anti-RAGE F(ab')(2) SPECT successfully identified early accelerated disease in diabetes mellitus for age-matched ApoE(-/-) mice and quantified RAGE expression over a range of lesion severities.