嵌合抗原受体T细胞经不同给药途径对小鼠心肌梗死后心律失常的影响

Effects of different administration routes of chimeric antigen receptor T cells on arrhythmias in mice with myocardial infarction

目的探究嵌合抗原受体(chimeric antigen receptor,CAR)T细胞对心肌梗死的治疗作用,并观察不同给药途径对CAR-T细胞心脏毒性的影响。方法将成功建立心肌梗死模型的24只SCID Beige免疫缺陷小鼠随机均分为Hank’s平衡盐溶液(HBSS)组、CAR-TIM组、CAR-TIV组及CAR-TIMIV组(均n=6),另设Sham组(n=6)。Sham组、HBSS组、CAR-TIM组和CAR-TIMIV组于造模后第7天,心肌局部注射HBSS或CAR-T细胞;Sham组、HBSS组、CAR-TIV组和CAR-TIMIV组于造模后第7天、第14天,尾静脉注射HBSS或CAR-T细胞。造模28 d后,观察小鼠电生理指标,并对心肌组织进行Masson染色,计算心肌梗死面积。结果与Sham组相比,HBSS组心肌梗死面积显著增加(P<0.05),心律失常发生率未明显升高。与HBSS组相比,不同给药途径的CAR-T细胞治疗组的心肌梗死面积均显著缩小(均P<0.05),心律失常发生率均显著升高(均P<0.05)。CAR-TIV组与CAR-TIM组间心肌梗死的治疗效果和心律失常发生率无显著差异;CAR-TIMIV组较CAR-TIV组,心肌梗死面积显著降低(P<0.05),两组间心律失常发生率无显著差异。结论静脉联合心肌局部注射CAR-T细胞可有效降低心肌梗死面积,但增加心律失常发生率,其机制有待进一步研究。

Objective To investigate the therapeutic effect of chimeric antigen receptor(CAR) T cells on myocardial infarction(MI) and observe the impact of different administration routes on CAR-T cell cardiac toxicity. Methods Twenty-four SCID Beige immunodeficient mice, which successfully established a myocardial infarction model, were randomly divided into Hank's balanced salt solution(HBSS) group, CAR-TIM group, CAR-TIV group, and CAR-TIMIV group(n=6 for each group). In addition,a Sham group(n=6) was set up. The Sham group, HBSS group, CAR-TIM group, and CAR-TIMIV group were injected with HBSS or CAR-T cells via intramyocardial injection on the 7th day after modeling. The Sham group, HBSS group, CAR-TIV group, and CAR-TIMIV group were injected with HBSS or CAR-T cells via tail vein injection on the 7th day and 14th day after modeling. After28 days of modeling, the electrical physiological indicators of the mice were observed, and the myocardial tissues were subjected to Masson staining to calculate the area of myocardial infarction. Results Compared with the Sham group, the HBSS group had significant increases in myocardial infarction size and incidence of arrhythmia(P<0.05). Compared with HBSS group, different routes of CAR-T cell therapy significantly reduced the area of myocardial infarction(all P<0.05) and significantly increased the incidence of arrhythmia(all P<0.05). There was no significant difference in the effect of CAR-TIV and CAR-TIM groups on the area of myocardial infarction and the incidence of arrhythmia. Compared with the CAR-TIV group,the area of myocardial infarction significantly reduced in the CAR-TIMIV group(P<0.05), with no significant difference in the incidence of arrhythmia between the two groups. Conclusions Intravenous and local myocardial injection of CAR-T cells can effectively reduce the myocardial infarction area but increase the incidence of arrhythmia. The mechanism needs further study.