BALB/c小鼠格雷夫斯病模型靶向TSHR和ICAM-1治疗的研究  

Targeting TSHR and ICAM-1 for treatment of Graves′ disease in BALB/c mice

作　　者：郑薇[1] 王萱 李宁[1] 刘金剑[2] 王深[1] 谭建[1] 贾强[1] 孟召伟[1] 芮忠颖 Zheng Wei;Wang Xuan;Li Ning;Liu Jinjian;Wang Shen;Tan Jian;Jia Qiang;Meng Zhaowei;Rui Zhongying(Department of Nuclear Medicine,Tianjin Medical University General Hospital,Tianjin 300052,China;Institute of Radiation Medicine,Chinese Academy of Medical Sciences,Tianjin 300192,China)

机构地区：[1]天津医科大学总医院核医学科,天津300052 [2]中国医学科学院放射医学研究所,天津300192

出　　处：《中华核医学与分子影像杂志》2022年第6期363-367,共5页Chinese Journal of Nuclear Medicine and Molecular Imaging

基　　金：国家自然科学基金(81601523);天津市卫生健康科技项目(ZC20181);天津医科大学总医院青年孵育基金(ZYYFY2019027)。

摘　　要：目的:探讨靶向促甲状腺激素受体(TSHR)和细胞间黏附分子-1(ICAM-1)治疗格雷夫斯病(GD)的新方法。方法:设计合成TSHR的小干扰RNA(siRNA)及ICAM-1单克隆抗体(mAb)。30只GD模型鼠按随机数字表法分为siRNA治疗组、ICAM-1 mAb治疗组及未治疗组,另取10只正常小鼠作为空白对照。治疗前、后测定小鼠血清甲状腺素(T_(4))、促甲状腺激素(TSH)、TSH受体刺激性抗体(TSAb)、TSH刺激阻断性抗体(TSBAb)水平,治疗结束后测定各组小鼠体质量、心率,评估甲状腺摄取^(99)Tc^(m)O_(4)^(-)能力、甲状腺大小及病理变化。采用两独立样本t检验、配对t检验及单因素方差分析处理数据。结果:3次治疗后,siRNA组、ICAM-1 mAb组小鼠体质量均低于正常小鼠(F=3.50,P=0.025),心率均低于未治疗组GD模型鼠(F=24.73,P<0.001),其中siRNA组心率下降明显,接近正常小鼠。3次治疗后,siRNA组、ICAM-1 mAb组小鼠血清T_(4)[(27.58±1.94)、(27.24±3.50)μg/L]、TSAb[(331.44±43.38)、(275.16±45.80)mU/L]、TSBAb[(13.94±1.11)、(14.59±1.02)mU/L]水平均较治疗前明显下降[T_(4):(65.71±6.89)、(70.84±8.46)μg/L,TSAb:(457.33±45.85)、(443.91±42.32)mU/L,TSBAb:(15.83±5.92)、(17.05±6.16)mU/L;t值:4.45~10.87,均P<0.05],2组小鼠血清TSH水平[(0.13±0.05)、(1.46±0.34)mU/L]均较治疗前明显上升[(0.04±0.05)、(0.06±0.03)mU/L;t值:-2.22、-5.87,P值:0.007、<0.001],ICAM-1 mAb组小鼠TSH升高幅度及TSAb降低幅度高于siRNA组(t值:1.03、-1.63,P值:0.002、0.031)。治疗后siRNA组、ICAM-1 mAb组小鼠均见甲状腺部分腺叶摄取^(99)Tc^(m)O_(4)^(-)能力减低,相应腺叶肿大程度缩小。治疗组小鼠甲状腺病理可见甲状腺滤泡吸收空泡减少,胶质稀薄现象有所改善。小鼠心、肝、肾病理未见明显损伤。结论:靶向TSHR的siRNA及ICAM-1 mAb均对GD模型鼠有治疗作用,在控制心率方面siRNA效果更好,在升高TSH及降低TSAb方面ICAM-1 mAb效果更好。上述治疗方法安全、有效,可以为GDObjective To explore new methods of treating Graves′disease(GD)by targeting thyroid stimulating hormone receptor(TSHR)and intercellular adhesion molecule-1(ICAM-1).Methods The small interfering RNA(siRNA)targeting TSHR and the ICAM-1 monoclonal antibody(mAb)were designed and synthesized.Thirty GD model mice were randomly divided into siRNA treatment group,ICAM-1 mAb treatment group,and untreated GD group(10 mice in each group),and 10 normal mice were taken as blank control.Serum thyroxine(T_(4)),thyroid stimulating hormone(TSH),TSH receptor-stimulating antibody(TSAb)and TSH-stimulation blocking antibody(TSBAb)were measured before and after treatment.At the end of the treatment,body mass and heart rate of mice in each group were measured,and thyroid uptake of ^(99)Tc^(m)O_(4)^(-),thyroid size and pathological changes were evaluated.Independent-sample t test,paired t test and one-way analysis of variance were used to analyze data.Results After three treatments,the body mass of mice in siRNA group and ICAM-1 mAb group were significantly lower than that of normal mice(F=3.50,P=0.025);the heart rates of the mice in two groups were significantly lower than that of untreated GD mice(F=24.73,P<0.001).Heart rate of mice treated with siRNA decreased significantly,close to that of normal mice.After treatment,the serum T_(4)((27.58±1.94)vs(65.71±6.89)μg/L,(27.24±3.50)vs(70.84±8.46)μg/L),TSAb((331.44±43.38)vs(457.33±45.85)mU/L,(275.16±45.80)vs(443.91±42.32)mU/L)and TSBAb((13.94±1.11)vs(15.83±5.92)mU/L,(14.59±1.02)vs(17.05±6.16)mU/L)levels of mice in both siRNA group and ICAM-1 mAb group significantly decreased(t values:4.45-10.87,all P<0.05),while the serum TSH levels of mice in two groups significantly increased((0.13±0.05)vs(0.04±0.05)mU/L,(1.46±0.34)vs(0.06±0.03)mU/L;t values:-2.22,-5.87,P values:0.007,<0.001).The elevated TSH level and decreased TSAb level of mice treated with ICAM-1 mAb were significantly different from those treated with siRNA(t values:1.03,-1.63,P values:0.002,0.031).After treatment

关 键 词：格雷夫斯病 RNA 小分子干扰 受体 促甲状腺素 抗体 单克隆 胞间黏附分子1 疾病模型 动物 小鼠 

分 类 号：R817.5[医药卫生—影像医学与核医学]