泡球蚴感染诱导Kupfter细胞表达PD-L1抑制大鼠肝移植急性排斥反应的机制研究
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摘要
目的：探讨枯否细胞(Kupffer cells, KCs)表达PD-L1在泡球蚴(E.m)感染抑制大鼠肝移植(OLT)急性排斥反应中的作用。方法：(1)建立BN大鼠感染E.m的动物模型。实验分三组：A组皮下注射接种感染组；B组开腹直视肝穿刺注射感染组；C组经皮肝脏穿刺接种感染组。3-4周龄BN大鼠每组20只,每只接种2000头节/ml的E.m悬液0.2ml。感染3个月后观察各组的感染率,死亡率,ELISA检测Th1类细胞因子干扰素γ(interferon-y, IFN-y)、和Th2类细胞因子白介素10(interleukin-10, IL-10)在血浆中的表达情况。(2)采用Kamada“二袖套法”建立大鼠OLT动物模型。实验分两组,对照组：Lewis (LEW)→Brown Norway (BN)(E.m-)n=30；实验组：LEW→BN(E.m+)n=30。术后各组随即分出6只大鼠观察其生存天数,于OLT术后1、3、5及7天分别处死6只大鼠取外周血及肝脏组织标本。光镜观察移植肝脏的病理学排斥分级；全自动生化分析仪检测外周血浆天冬氨酸转移酶(aspartate aminotransferase,AST)和总胆红素(total bilirubin,TBIL);ELISA检测Thl类细胞因子干扰素γ(interferon-γ, IFN-γ)、和Th2类细胞因子白介素10(interleukin-10,IL-10)在血浆中的表达情况,免疫组织化学检测PD-L1在两组移植肝脏中的表达情况,real-time PCR检测两组移植肝中PD-L1mRAN的表达。(3)分离培养实验组(E.m+)和对照组(E.m-)术后7天移植肝脏中KCS分别记为KCsE.m-和KCsE.m-,分离培养正常BN大鼠脾脏T淋巴细胞(TCs),单独或混合培养。实验分四组：KCs实验组：KCsE.m+;KCs对照组：KCsE.m-;混合培养实验组：KCSE.m++TCs;混合培养对照组：KCsE.m-+TCs;免疫组化检测KCs表面程序性死亡配体1(Programmed death ligand1, PD-L1)的表达情况。将KCs与TCs共同培养24h,MTT法检测TCs的增值,流式细胞计数法检测TCs凋亡情况,ELISA检测培养上清液中IFN-γ和IL-10的含量。结果：(1)观察皮下注射成功建立了Em感染大鼠模型,其中死亡0只,死亡率0%(0/20),感染率60%(12/20只),ELISA检测三种方法感染大鼠外周血中IFN-γ、IL-10的浓度无差异(P<0.05)。(2)采用改良的Kamad"二袖套法”成功建立了稳定的大鼠原位肝移植动物模型。发现实验组最长存活26天,平均生存天数10.2±2.13天。而对照组组于12天内全部死亡,平均生存天数22.5±4.04天,两组差异明显(P<0.05)。对照组大鼠术后血浆AST和TBIL呈现进行性升高,而实验组则上升缓慢,两组差异明显(P<0.05)。ELISA结果显示：对照组术后7天,血浆中INF-γ(分别为210.68±16.82、170.97±14.64和126.4±15.57,pg/ml)的浓度明显低于对照组(分别为753.50±12.68、509.83±17.91和427.97±13.49,pg/ml)组,而IL-10(371.13±17.63,pg/ml)的浓度则明显高于对照组(187.48±12.89,pg/ml)(P<0.05)。免疫组织化学结果显示：实验组术后第7天PD-L1呈强阳性表达并且表达范围广；而在对照组PD-L1表达始终较弱,两组比较有明显差异(P<0.05)。Real-time PCR检测PD-L1mRNA在实验组术后第7天呈强阳性表达并且表达范围广；而在对照组表达始终较弱,两组比较有明显差异(P<0.05)。(3)KCsE.m+组中PD-L1的表达明显高于KCsE.m-(P<0.05)。KCSE.m++TCs组中TCs的增殖(13258.34±951.26cpm)明显低于KCSE.m-+TCs组(3047.98±101.42cpm,P<0.05),而其凋亡率(8.83±0.37%)却显著高于后者(1.34±0.16%,P<0.05)。KCsEm++TCs组上清液中INF-γ的含量明显低于KCsE.m-+TCs组(P<0.05),但IL-10在KCs.m-+TCs组(108.8±12.89pg/ml)明显高于KCsE.m-+TCs组(49.13±17.63pg/ml,P<0.05)。结论：泡球蚴感染后可能通过上调KCs表面PD-L1的表达抑制TCs的增值促进TCs的凋亡进而减缓了肝移植急性排斥反应的发生
Objective:To explore the potential role of programmed death-ligand1(PD-L1) expressed by the Kupffer cells in alleviating the liver transplantation acute rejection in echinococcus multilocularis infected rats. Methods:(1)The animals were divided into three groups:group A was injected subcutaneously infected group; Group B was infected of E.m by laparotomy. group C, percutaneous puncture E.m inoculation of liver. BN rats were3-4weeks old (n=20), each inoculated with2000Festival/ml of the Em suspension0.2ml. Observed rate of infection of each group at3months after infection, mortality, ELISA detection expression of Thl cytokines interferon gamma(IFN-y) and Th2cytokines white interleukin-10(IL-10) in the plasma.(2)The animal model of OLT were established with Kamada "double takes method" and divided control group:Lewis to BN (E.m uninfected) and experimental group:Lewis to BN (E.m infected) with30rats in each group. Six rats were randomly chosen in each group to observe the survival days. Six rats were respectively sacrificed at post-operative dayl,3,5and7and the peripheral blood and liver tissues samples were collected in each group. The pathological liver rejection classification was microscopically observed; peripheral level of aspartate aminiotransferase (AST) and total bilirubin (TBIL) levels were detected by Automatic Biochemical Analyzer. Plasma levels of Interluekin-10(IL-10) and interferon-y were detected by ELISA. The expression of PD-L1in transplanted liver tissue was detected by Immunohistochemistry and the expression of PD-L1m RNA was detected by real-time PCR assay.(3)Separation transplanted iver KCs of the experimental group and control group after7days and numbered with KCsE.m+and KCsE.m-. Meanwhile, separated and cultured splenic T lymphocytes (TCs) of normal BN rat. Cultured alone or mixed and which were divided into four groups:KCs experimental group:KCsE.m+; KCs the control group:KCsE.m-; mixed culture experimental groups:KCsE.m+TCs; mixed culture in the control group:KCsE.m-+TCs. Co-culture the KCs and TCs for24h and detect the proliferation of TCs by MTT; apoptosis of TCs by cytometry, and expression level of IL-10and IFN-y in supernate by ELISA. Results:(1)Observing the subcutaneous successful E.m infected rat model, and the death number was0, mortality was0%(0/20), the infection rate of60%(12/20), ELISA detection of three methods of three groups and the results show that peripheral serum of IFN-y, IL-10was no difference (P<0.05);(2)the steady and successful model of orthotropic liver transplantation was established in rats by using the modified Kamada method. The longest survival time in experimental group was26days with the median survival time was10.2±2.13; However by showing statistical significance, the longest survival time in control group was12days with the median survival time was22.5±4.04days. The post-operative levels of AST and TBIL in control group showed progressive increases and only a slight increase in experimental group. At the post-operative day7, the plasma level of IFN-y was significantly lower and the IL-10level was significantly higher in experimental group than that were in control group. PD-L1was highly expresses with wide extent in experimental group, however in control group, it was weakly expressed. In line with this, the PD-L1m RNA was higly expressed with wider extent in experimental group than that was in control group and showed statistical significance.(3)The PD-L1expression of group KCsE.m+was higher than KCsE.m-(P<0.05), the TCs proliferation in KCsE.m++TCs was (13258.34±951.26cpm), and lower than group KCsE.m-+TCs, which was (3047.98±101.42cpm), P<0.05. However, the apoptosis rate of group KCsE.m++TCs (8.83±0.37%)was significantly higher than that was in group KCsE.m-+TCs(1.34±0.16%), P<0.05. The expression of the level of the IFN-y in group KCsE.m++TCs of co-culture fluid was significantly lower than group KCsE.m-+TCs, P<0.05. However, the former expression (108.8±12.89pg/ml) of IL-10level was significantly higher than group KCsE.m-+TCs(49.13±17.63pg/ml), P<0.05. Conclusion: Echinococcus multilocularis infection may alleviate the post-liver transplantation acute rejection by up-regulating the level of PD-L1in KCs and inhibit the proliferation and accelerate the apoptosis of TCs.
Objective:To explore the potential role of programmed death-ligand1(PD-L1) expressed by the Kupffer cells in alleviating the liver transplantation acute rejection in echinococcus multilocularis infected rats. Methods:(1)The animals were divided into three groups:group A was injected subcutaneously infected group; Group B was infected of E.m by laparotomy. group C, percutaneous puncture E.m inoculation of liver. BN rats were3-4weeks old (n=20), each inoculated with2000Festival/ml of the Em suspension0.2ml. Observed rate of infection of each group at3months after infection, mortality, ELISA detection expression of Thl cytokines interferon gamma(IFN-y) and Th2cytokines white interleukin-10(IL-10) in the plasma.(2)The animal model of OLT were established with Kamada "double takes method" and divided control group:Lewis to BN (E.m uninfected) and experimental group:Lewis to BN (E.m infected) with30rats in each group. Six rats were randomly chosen in each group to observe the survival days. Six rats were respectively sacrificed at post-operative dayl,3,5and7and the peripheral blood and liver tissues samples were collected in each group. The pathological liver rejection classification was microscopically observed; peripheral level of aspartate aminiotransferase (AST) and total bilirubin (TBIL) levels were detected by Automatic Biochemical Analyzer. Plasma levels of Interluekin-10(IL-10) and interferon-y were detected by ELISA. The expression of PD-L1in transplanted liver tissue was detected by Immunohistochemistry and the expression of PD-L1m RNA was detected by real-time PCR assay.(3)Separation transplanted iver KCs of the experimental group and control group after7days and numbered with KCsE.m+and KCsE.m-. Meanwhile, separated and cultured splenic T lymphocytes (TCs) of normal BN rat. Cultured alone or mixed and which were divided into four groups:KCs experimental group:KCsE.m+; KCs the control group:KCsE.m-; mixed culture experimental groups:KCsE.m+TCs; mixed culture in the control group:KCsE.m-+TCs. Co-culture the KCs and TCs for24h and detect the proliferation of TCs by MTT; apoptosis of TCs by cytometry, and expression level of IL-10and IFN-y in supernate by ELISA. Results:(1)Observing the subcutaneous successful E.m infected rat model, and the death number was0, mortality was0%(0/20), the infection rate of60%(12/20), ELISA detection of three methods of three groups and the results show that peripheral serum of IFN-y, IL-10was no difference (P<0.05);(2)the steady and successful model of orthotropic liver transplantation was established in rats by using the modified Kamada method. The longest survival time in experimental group was26days with the median survival time was10.2±2.13; However by showing statistical significance, the longest survival time in control group was12days with the median survival time was22.5±4.04days. The post-operative levels of AST and TBIL in control group showed progressive increases and only a slight increase in experimental group. At the post-operative day7, the plasma level of IFN-y was significantly lower and the IL-10level was significantly higher in experimental group than that were in control group. PD-L1was highly expresses with wide extent in experimental group, however in control group, it was weakly expressed. In line with this, the PD-L1m RNA was higly expressed with wider extent in experimental group than that was in control group and showed statistical significance.(3)The PD-L1expression of group KCsE.m+was higher than KCsE.m-(P<0.05), the TCs proliferation in KCsE.m++TCs was (13258.34±951.26cpm), and lower than group KCsE.m-+TCs, which was (3047.98±101.42cpm), P<0.05. However, the apoptosis rate of group KCsE.m++TCs (8.83±0.37%)was significantly higher than that was in group KCsE.m-+TCs(1.34±0.16%), P<0.05. The expression of the level of the IFN-y in group KCsE.m++TCs of co-culture fluid was significantly lower than group KCsE.m-+TCs, P<0.05. However, the former expression (108.8±12.89pg/ml) of IL-10level was significantly higher than group KCsE.m-+TCs(49.13±17.63pg/ml), P<0.05. Conclusion: Echinococcus multilocularis infection may alleviate the post-liver transplantation acute rejection by up-regulating the level of PD-L1in KCs and inhibit the proliferation and accelerate the apoptosis of TCs.
引文
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