阻断巨噬细胞介导的PD1/ PD-L1 通路对小鼠结核复发的抑制作用

doi:10.3969/j. issn. 1671 -7856. 2018. 04. 009

首页 > 过刊浏览>2018年第28卷第4期 >50-58. DOI:10.3969/j. issn. 1671 -7856. 2018. 04. 009

阻断巨噬细胞介导的PD1/ PD-L1 通路对小鼠结核复发的抑制作用
DOI:
                        10.3969/j. issn. 1671 -7856. 2018. 04. 009
                    
作者:
                        孙萌萌孙萌萌
中国医学科学院医学实验动物研究所,国家中医药管理局人类疾病动物模型三级实验室,卫计委人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室,北京市人类重大疾病实验动物模型,中国医学科学院结核病中心,北京 100021
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秦川秦川
中国医学科学院医学实验动物研究所,国家中医药管理局人类疾病动物模型三级实验室,卫计委人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室,北京市人类重大疾病实验动物模型,中国医学科学院结核病中心,北京 100021
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唐军唐军
中国医学科学院医学实验动物研究所,国家中医药管理局人类疾病动物模型三级实验室,卫计委人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室,北京市人类重大疾病实验动物模型,中国医学科学院结核病中心,北京 100021
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占玲俊占玲俊
中国医学科学院医学实验动物研究所,国家中医药管理局人类疾病动物模型三级实验室,卫计委人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室,北京市人类重大疾病实验动物模型,中国医学科学院结核病中心,北京 100021
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作者单位:(中国医学科学院医学实验动物研究所,国家中医药管理局人类疾病动物模型三级实验室,卫计委人类疾病比较医学重点实验室, 新发再发传染病动物模型研究北京市重点实验室,北京市人类重大疾病实验动物模型,中国医学科学院结核病中心,北京 100021)
作者简介:13011825389@163. com
通讯作者:
中图分类号:R-33
基金项目:中央级公益性事业单位院基本业务费(2016ZX310183-2);中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-031)

Blockage of macrophage-mediated PD1/ PD-L1 pathways inhibits tuberculosis relapse in mice

Author:

SUN Mengmeng
SUN Mengmeng
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS);Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine; Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infections; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases; Tuberculosis (TB) Center, Chinese Academy of Medical Sciences, Beijing 100021, China
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QIN Chuan
QIN Chuan
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS);Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine; Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infections; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases; Tuberculosis (TB) Center, Chinese Academy of Medical Sciences, Beijing 100021, China
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TANG Jun
TANG Jun
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS);Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine; Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infections; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases; Tuberculosis (TB) Center, Chinese Academy of Medical Sciences, Beijing 100021, China
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ZHAN Lingjun
ZHAN Lingjun
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS);Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine; Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infections; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases; Tuberculosis (TB) Center, Chinese Academy of Medical Sciences, Beijing 100021, China
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Affiliation:

(Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS);Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine; Key Laboratory of Human Disease Comparative Medicine, Ministry of Health; Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infections; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases; Tuberculosis (TB) Center, Chinese Academy of Medical Sciences, Beijing 100021, China)

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摘要:

目的利用功能性PD-L1(programmed cell death ligand-1,PD-L1)单抗阻断巨噬细胞介导的PD1/PD-L1 通路,研究其对小鼠结核治疗后复发的免疫干预作用和机制?方法 106 CFU H37Rv 经尾静脉感染C57BL/6 雌性小鼠获得结核的急性感染,两周之后分别给予异烟肼(10 mg/ kg)和异烟肼联合PD-L1 单抗(每只50 μg)连续治疗四周,获得潜伏感染,在潜伏期用TNF-α 抗体(每只50 μg)诱导四周使其复发?通过对各时间点的肺?脾和肝组织病理及荷菌量的定量分析,探讨PD-L1 单抗对小鼠活动性结核及结核复发的干预作用?利用体外实验,进一步阐明敲低PD-L1 对结核菌感染的巨噬细胞凋亡的影响?结果小鼠感染后,前两周肺?脾和肝荷菌量较高(3 ~4 Lg CFU/ mL)?肉芽肿病变较重,表现为活动性结核,异烟肼和异烟肼联合PD-L1 单抗分别治疗四周之后,肺?脾和肝荷菌量均较模型对照组显著性地降低,肉芽肿样病变也显著减轻,但是两个治疗组之间没有显著性的差异?而在复发期,相比较于异烟肼治疗组, 异烟肼联合PD-L1 单抗治疗组能够显著降低复发期组织荷菌量,减轻病理病变?体外实验证实:用PD-L1 抗体或siRNA 敲低巨噬细胞上PD-L1,结果发现二者都能能促进结核感染的巨噬细胞凋亡?结论功能性的PD-L1 抗体可以抑制结核复发,敲低巨噬细胞上PD-L1 或阻断PD1/ PD-L1 通路能促进巨噬细胞凋亡,提示阻断PD-L1 能够有效的协助异烟肼治疗结核病,并且显著地抑制结核的复发?

关键词:PD-L1 抗体干预;小鼠结核模型;结核复发;巨噬细胞凋亡

Abstract:

Objective To study the immune intervention effect and mechanism of blockage of macrophage-mediated PD1 / PD-L1 pathways with functional PD-L1(programmed cell death ligand-1,PD-L1)monoclonal antibody upon tuberculosis (TB) relapse in mice. Methods Female C57BL/6 mice were infected by tail vein injection of 106 CFU M. tuberculosis H37Rv to obtain active TB infection. Two weeks postinfection, the mice in different groups were administered isoniazid (10 mg/ kg) (group ISO) and isoniazid combined with PD-L1 monoclonal antibody (50 μg/ each) (group ISO +PD-L1) respectively, continued for four weeks to obtain latent infection. The subsequent relapse was monitored. Among the treatment groups, the TB relapse was induced by TNF-α antibody (50 ug/ each) for four weeks from the beginning of latent stage. At each scheduled time point, bacterial loads and pathological changes in the lung, spleen and liver were quantitatively analyzed, thereby, the in vivo intervention effect of PD-L1 monoclonal antibody on tuberculosis recurrence in mice was revealed. The in vitro experiment was further explored whether knock-down the expression of PD-L1 on the infected macrophages could accerlate the macrophage apoptosis. Results The bacterial burden reached 3 -4 Lg (CFU/mL), and granuloma lesions were extensive in the lung, spleen and liver in the all infected groups, which appeared as active TB stage at 2nd week postinfection. After treated, the bacterial burden of the lung, spleen and liver was decreased, and the pathological lesions alleviated in the group ISO and group ISO + PD-L1, compared with the model control group, showing significant differences, but there was no significant difference between the two treatment groups. However, compared with the group ISO, the group ISO + PD-L1 had a significantly lower bacterial load and milder pathological lesions during the relapse period. Futhermore, knock-down the expression of PD-L1 on macrophages with anti-PD-L1 or PD-L1-siRNA promoted apoptosis in macrophages. Conclusions Blockade of the PD1/ PD-L1 pathway by PD-L1 functional antibody can inhibit TB relapse in mice, and knock-down the expression of PD-L1 on macrophages or PD1/ PD-L1 pathway with functional antibody can promote apoptosis in macrophages, which together indicate that PD-L1 blockage can effectively promote isoniazid treatment of TB and remarkably inhibit the recurrence of TB in mice.

Key words:blockade with PD-L1 functional antibody; mice model of tuberculosis; tuberculosis relapse; macrophage apoptosis

引用本文

孙萌萌,秦川,唐军,占玲俊.阻断巨噬细胞介导的PD1/ PD-L1 通路对小鼠结核复发的抑制作用[J].中国比较医学杂志,2018,28(4):50~58.

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收稿日期:2017-11-12
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在线发布日期: 2018-05-22
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