1.Department of Hepatobiliary & Hydatid Disease, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830054, China;
2.State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Uygur Autonomous Region, Urumqi 830054, China
Abstract：Objective To observe the effect of the absence of natural killer (NK) cells and CD8+T cells on the liver function in mice infected with metacestode of Echinococcus multilocularis. Methods A total of 30 SPF grade female C57BL/6 mice aged six to eight weeks and with a body weight of 18-20 g were selected and divided into control group, metacestode of Echinococcus multilocularis infection group, NK cell clearance group, NK cell clearance control group, CD8+T cell clearance group, and CD8+T cell clearance control group according to random number table method, with five mice in each group. Metacestode of Echinococcus multilocularis infection group, NK cell clearance group, NK cell clearance control group, CD8+T cell clearance group, CD8+T cell clearance control group were all injected into the portal vein with the scolices of Echinococcus multilocularis Leuckart (10 scolices/μl, 200 μl), and the control group was injected into the portal vein with equal amount of normal saline. At the fourth week of the experiment, the NK cell clearance group was intraperitoneally injected with NK cell clearance antibody, 100 μg each time, once a week, while the NK cell clearance control group was intraperitoneally injected with the same amount of IgG2a homologous control antibody; CD8+T cell clearance group was intraperitoneally injected with CD8+T cell clearance antibody 200 μg each time, once a week, while CD8+T cell clearance control group was intraperitoneally injected with the same amount of IgG2b homologous control antibody. At the 12th week of the experiment, the peripheral blood of six groups was collected, the peripheral blood plasma was separated, and the liver and kidney function indexes of total protein (TP), alkaline phosphatase, glutamic-pyruvic transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), albumin (ALB), lactate dehydrogenase, uric acid, urea, and creatinine were detected. Results The levels of GPT and GOT in the peripheral blood of metacestode of Echinococcus multilocularis infection group were higher than those of control group, and the differences were statistically significant (P＜0.05 or P＜0.01). The levels of GPT and GOT in peripheral blood of NK cell clearance group were higher than those of NK cell clearance control group, and TP and ALB were lower than those of NK cell clearance control group, the differences were statistically significant (P＜0.05 or P＜0.01). The level of TP inperipheral blood of CD8+T cell clearance group was lower than that of CD8+T cell clearance control group, and the difference was statistically significant (P＜0.05). Conclusion Metacestode of Echinococcus multilocularis infection can cause liver function damage to a certain extent, especially in the state of NK cell depletion.
[1] Wen H，Vuitton L，Tuxun T，et al. Echinococcosis：Advances in the 21st Century [J]. Clin Microbiol Rev，2019，32（2）：e00075- 18.
[2] Graeter T，Bao HH，Shi R，et al. Evaluation of intrahepatic manifestation and distant extrahepatic disease in alveolar echinococcosis [J]. World J Gastroenterol，2020，26（29）：4302- 4315.
[3] Kern P，Menezes da Silva A，Akhan O，et al. The Echinococcoses：Diagnosis，Clinical Management and Burden of Disease [J]. Adv Parasitol，2017，96：259-369.
[4] Hemphill A，Stadelmann B，Rufener R，et al. Treatment of ech- inococcosis：albendazole and mebendazole——what else？[J].Parasite，2014，21：70.
[5] Aji T，Dong JH，Shao YM，et al. Exvivo liver resection and autotransplantation as alternative to allotransplantation for end-stage hepatic alveolar echinococcosis [J]. J Hepatol，2018，69（5）：1037-1046.
[6] Abulizi A，Shao Y，Aji T，et al. Echinococcus multilocularis inoculation induces NK cell functional decrease through high expression of NKG2A in C57BL/6 mice [J]. BMC Infect Dis，2019，19（1）：792.
[7] Zhang C，Shao Y，Yang S，et al. T-cell tolerance and exhaustion in the clearance of Echinococcus multilocularis： role of inoculum size in a quantitative hepatic experimental model [J]. Sci Rep，2017，7（1）：11153.
[8] Liu YM，Tian FM，Shan JY，et al. Kupffer Cells：Important Participant of Hepatic Alveolar Echinococcosis [J]. Front Cell Infect Microbiol，2020，10：8.
[9] Nono JK，Pletinckx K，Lutz MB，et al. Excretory/secretory- products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro [J]. PLoS Negl Trop Dis，2012；6（2）：e1516.
[10] Wang J，Goepfert C，Mueller N，et al. Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions [J]. Immunology，2018， 154（1）：76-88.
[11] Tuxun T，Apaer S，Ma HZ，et al. The Potential Role of Th9 Cell Related Cytokine and Transcription Factors in Patients with Hepatic Alveolar Echinococcosis [J]. J Immunol Res，2015，2015：895416.
[12] Wang J，Müller S，Lin R，et al. Depletion of FoxP3+ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity [J]. Immun Inflamm Dis，2017，5（4）：435-447.
[13] Webb LM，Tait Wojno ED. The role of rare innate immune cells in Type 2 immune activation against parasitic helmin- ths [J]. Parasitology，2017，144（10）：1288-1301.
[14] Doyle EH，Aloman C，El-Shamy A，et al. A subset of liver resident natural killer cells is expanded in hepatitis C-infected patients with better liver function [J]. Sci Rep，2021， 11（1）：1551.
[15] Varchetta S，Mele D，Mantovani S，et al. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection [J]. Hepatology，2012，56（3）：841-849.
[16] Guo X，Xu Y，Luo W，et al. Programmed cell death protein-1（PD-1）protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice [J]. BMC Pediatr，2021，21（1）：317.
[17] 阿依努尔·艾尔肯，阿卜杜艾尼·啊卜力孜，塔来提·吐尔干，等.阻断NKG2A共抑制分子在抗肿瘤免疫效应中的研究进展[J].中国医药科学，2022，12（4）：29-33.
[18] Bellanger AP，Mougey V，Pallandre JR，et al. Echinococcus multilocularis vesicular fluid inhibits activation and proliferation of natural killer cells [J]. Folia Parasitol（Praha），2017，64：2017.029.
[19] Zhang CS，Lin RY，Li ZD，et al. Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model [J]. Hepatology，2020，71（4）：1297-1315.
[20] André P，Denis C，Soulas C，et al. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells [J]. Cell，2018，175（7）： 1731-1743.
[21] Burrack KS，Tan JJ，McCarthy MK，et al. Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells [J]. PLoS Pathog，2015，11（10）：e1005191.
[22] Yang HC，Xing ZK，Shao H，et al. The expression of cytokeratin and apoptosis-related molecules in echinococcosis related liver injury [J]. Mol Biochem Parasitol，2022，248：111455.
[23] Bogdanos DP，Gao B，Gershwin ME. Liver immunology [J]. Compr Physiol，2013，3（2）：567-598.
[24] Zhang Y，Wu Y，Shen W，et al. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis（Review）[J]. Mol Med Rep，2022，25（6）：208.
[25] Zhang X，Zhu L，Zhou Y，et al. Interference with KCTD9 inhibits NK cell activation and ameliorates fulminant liver failure in mice [J]. BMC Immunol，2018，19（1）：20.
[26] 张伶慧，陈根，种世桂，等.多房棘球蚴病中免疫细胞调控机制的研究进展[J].中国寄生虫学与寄生虫病杂志，2022，40（1）：109-113，120.
[27] 杨康洁，芦永良，鄂维建.基于PD-1/PD-L1信号通路的肝棘球蚴病免疫逃逸研究[J].临床肝胆病杂志，2023， 39（1）：218-225.
[28] 侯昕伶，李亮，李玲慧，等.泡球蚴感染对小鼠脾脏CD8+ T细胞免疫功能耗竭的影响[J].中国血吸虫病防治杂志，2020，32（6）：591-597，604.
京公网安备 11010502046598号