干预供肝CIITA与MyD88基因表达抑制大鼠肝移植排斥反应的实验研究
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摘要
第一部分纳米载体HGPAEs的制备及检测
目的：制备纳米载体组氮酸接枝聚(β-氨基酯)(HGPAEs)并观察其体内应用的安全性与有效性。方法：制备纳米载体组氨酸接枝聚(β-氨基酯)(HGPAEs),并对其进行性能测试；设置生理盐水组、纳米载体组和纳米载体质粒组,经门静脉注射体内转染大鼠肝脏,采取转染后第一天和第三天肝脏标本和静脉血,应用全波长酶标仪检测方法评价体内肝脏转染效果,并检测大鼠肝肾功能变化。结果：成功制备了纳米载体组氨酸接枝聚(β-氨基酯)(HGPAEs),经验证其具有作为基因载体的必备条件；第一天和第三天纳米载体质粒组的增强型绿荧光蛋白荧光强度均显著强于生理盐水对照组和纳米载体组(P<0.01),纳米载体质粒组第三天荧光强度强于第一天(P<0.01)；转染术后第一天,与正常值比较,各组ALT、AST均显著升高(P<0.01),但各组间比较无明显差异(P>0.05),转染术后第三天,各组生化指标均趋于正常。结论：纳米载体组氨酸接枝聚(β-氨基酯)制备简便,是一种安全高效的基因载体；以纳米载体为介导经门静脉注射的方法可使shRNA质粒在体内肝脏获得高效转染。
第二部分纳米载体介导沉默基因CⅡTA和MyD88表达的体内研究
目的：观察RNA干扰对免疫识别相关基因CⅡTA、MHC-Ⅱ和MyD88表达的抑制效果。方法：设置生理盐水对照组、纳米载体组、纳米载体pHK-shRNA组和纳米载体pC Ⅱ TA-shRNA组、纳米载体pMyD88-shRNA组、纳米载体pCⅡTA-pMyD88-shRNA组三个干预组,通过门静脉注射方法体内转染大鼠肝脏,转染后第三天取肝脏,以荧光定量PCR(?)western blot分别检测肝脏转染后CⅡTA、MHC-Ⅱ和MyD88基因mRNA和蛋白水平的表达变化。结果：荧光实时定量PCR和western blot检测显示纳米载体pC Ⅱ TA-shRNA组和纳米载体pCⅡTA-pMyD88-shRNA组CⅡTA和MHC Ⅱ基因mRNA和蛋白表达均较生理盐水组、纳米载体组和纳米载体pHK-shRNA组显著降低(P<0.01)；纳米载体pMyD88-shRNA组和纳米载体pC Ⅱ TA-pMyD88-shRNA组MyD88基因]mnRNA和蛋白表达较生理盐水组、纳米载体组和纳米载体pHK-shRNA组也有显著降低(P<0.01)；而纳米载体组、纳米载体pHK-shRNA组与生理盐水组之间CⅡTA、MHCⅡ和MyD88基因无论mRNA还是蛋白表达均无显著性差异(P>0.05)。结论：以纳米载体(HGPAEs)为介导经门静脉注射的方法,应用针对CⅡTA和MyD88的shRNA质粒转染大鼠肝脏,可显著抑制肝脏CⅡTA、MHC-Ⅱ和MyD88基因表达。
第三部分干预供体移植物抑制大鼠肝移植排斥反应的研究
目的：观察抑制供体肝脏CⅡTA和MyD88基因的表达对高应答大鼠原位肝移植模型移植排斥反应的影响,探讨其抗排斥机制。方法：建立高应答大鼠原位肝移植模型；设置生理盐水组、纳米载体组、pHK-shRNA纳米载体组、纳米载体pC Ⅱ TA-shRNA组、纳米载体pMyD88-shRNA组和纳米载体pCⅡTA-pMyD88-shRNA组,各组采用经门静脉注射的方法干预供体大鼠肝脏,干预后3天取肝脏进行肝移植,每组各12只大鼠,于移植术后第5天随机选取6只大鼠取静脉血和移植肝脏,病理切片确定排斥反应分级,分别采用荧光定量PCR和western blot检测肝中CⅡTA、MHC-Ⅱ和MyD88基因在mRNA和蛋白水平的表达变化,流式细胞术检测血中CD4/CD8细胞比例,ELISA去检测血清IL-2和IFN-γ浓度,并检测肝功能,其余6只用于观察存活期。结果：稳定建立高应答大鼠原位肝移植模型；与生理盐水组、纳米载体组和纳米载体pHK-shRNA组.相比,纳米载体pCⅡTA-shRNA组、纳米载体pMyD88-shRNA组和纳米载体pC Ⅱ TA-pMyD88-shRNA组大鼠存活时间明显延长(中位生存期16天、14天和21天vs10天、9天和8天,P<0.01),排斥反应病理分级明显降低(PPart I The preparation and test of nanometer vector HGPAEs
Objective:To prepare the nanometer vector HGPAEs and observe its safety and efficiency in vivo. Methods:The nanometer vector HGPAEs was prepared and tested. Normal saline group, nanometer group and nanometer vector pHK-shRNA control group were established for comparison and direct portal vein injection was performed to transfect liver. Liver specimens and blood were taken on the first day and the third day after transfection. Spectrofluorometer was used to detect the green fluorescent protein (EGFP) intensity and biochemical indicators like ALT, AST, TBIL. Crea and Urea were also detected. Results:The nanometer vector HGPAEs was successfully prepared and it was proved to be a nice vector for gene transfection. The EGFP intensity in liver of nanometer vector pHK-shRNA control group was significantly higher than normal saline group and nanometer vector control group both on the two experimental time points (P<0.01),and it showed that the intensity on the third day was higher than that on the first day in the plasmid group(P<0.01). Compared with normal value, the ALT and AST of all the three groups significantly increased on the first day after transfection (P<0.01). while there were no significant difference among the three groups themselves (P>0.05), and all those biochemical indicators became normal on the third day after transfection (P>0.05). Conclusions.-The nanometer vector HGPAEs was easy to be prepared and it was a promising gene transfer vector because it was effective and safe. Highly efficient liver transfection can be achieved through direct portal vein injection of the nanometer vector and plasmid DNA.
Part Ⅱ In vivo study of inhibiting genes CⅡTA and MyD88with the help of nanometer vector
Objective:To observe the inhibition effects of RNAi on immune recognition genes CIITA, MHC-Ⅱand MyD88. Methods:Totally6groups, including normal saline control group, nanometer vector control group, nanometer vector pHK-shRNA control group and nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group, received liver transfection through portal vein injection. Real time PCR and western blot were performed to detect the expression of C ⅡTA, MHC-Ⅱ and MyD88in liver3days after transfection. Results:Realtime PCR and western blot showed that, compared with normal saline control group, nanometer vector control group and nanometer vector pHK-shRNA control group, the expression of C Ⅱ TA and MHC-Ⅱ were obviously inhibited both in nanometer vector pC Ⅱ TA-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group(P<0.01), and the expression of MyD88was also significantly inhibited in both nanometer vector pMyD88-shRNA group and nanometer vector pCⅡTA-pMyD88-shRNA group(P<0.01), while there was no obvious expression difference of C Ⅱ TA, MHC-Ⅱ and MyD88among the three control groups (P>0.05)). Conclusions:Highly efficient liver transfection can be achieved through direct portal vein injection of the nanometer vector and plasmid DNA. The expression of C Ⅱ TA, MHC-Ⅱ and MyD88in rat liver can be obviously inhibited by plasmids containing shRNAs targeting C Ⅱ TA and MyD88.
Part Ⅲ The study of reducing transplantation rejection of rat liver by interferencing donor liver
Objective:To observe the effect of inhibiting the expression of CⅡ TA and MyD88of graft on transplantation rejection in high responder model of rat orthotopic liver transplantation and investigate its anti-rejection mechanism. Methods:The high responder model of rat orthotopic liver transplantation was established. There were7groups:normal saline control group, nanometer vector control group, nanometer vector pHK-shRNA control group, nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group, nanometer vector pC Ⅱ TA-pMyD88-shRNA group and CsA treating group. The donors in the first6groups received portal vein injection of normal saline or nanometer vector or nanometer vector and shRNA plasmid3days before transplantation.6recipients in each group were randomly chosen and sacrificed for their liver and blood as specimen5days after transplantation and the remaining6recipients were monitored for survival. The data of pathological rejection grading were collected by pathological examination, real-time PCR and western blot were used to test the mRNA and protein expression of CⅡTA, MHC-Ⅱ and MyD88in graft respectively, Flow Cytometry was used to test the ratio of CD4/CD8in blood, ELISA was used to observe the concentration of IL-2and IFN-y in serum, and liver function was also detected. Results:The high responder model of rat orthotopic liver transplantation was stably established. Compared to normal saline control group, nanometer vector control group and nanometer pHK-shRNA control group, the survival time of nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group extended significantly (median survival time16days,14days and21days vs1Odays,9days and8days, P<0.01), pathological rejection grading significantly depressed(P<0.01), the expressions of CⅡTA, MHC-Ⅱ and MyD88decreased significantly both on mRNA and protein level(P<0.01), the ratio of CD4/CD8in blood decreased obviously, the concentration of IL-2and IFN-γ in serum as well as liver function decreased significantly(P<0.01). Conclusion:High responder model of rat orthotopic liver transplantation is an ideal animal modelfor the study of liver transplantation rejection. Acute rejection reaction can be significantly relieved and survival time is extended by pretreatment of graft with portal vein injection of nanometer and shRNA plasmid targeting C Ⅱ TA and MyD88genes, which shows new way for both transplantation rejection research and clinical therapy.
目的：制备纳米载体组氮酸接枝聚(β-氨基酯)(HGPAEs)并观察其体内应用的安全性与有效性。方法：制备纳米载体组氨酸接枝聚(β-氨基酯)(HGPAEs),并对其进行性能测试；设置生理盐水组、纳米载体组和纳米载体质粒组,经门静脉注射体内转染大鼠肝脏,采取转染后第一天和第三天肝脏标本和静脉血,应用全波长酶标仪检测方法评价体内肝脏转染效果,并检测大鼠肝肾功能变化。结果：成功制备了纳米载体组氨酸接枝聚(β-氨基酯)(HGPAEs),经验证其具有作为基因载体的必备条件；第一天和第三天纳米载体质粒组的增强型绿荧光蛋白荧光强度均显著强于生理盐水对照组和纳米载体组(P<0.01),纳米载体质粒组第三天荧光强度强于第一天(P<0.01)；转染术后第一天,与正常值比较,各组ALT、AST均显著升高(P<0.01),但各组间比较无明显差异(P>0.05),转染术后第三天,各组生化指标均趋于正常。结论：纳米载体组氨酸接枝聚(β-氨基酯)制备简便,是一种安全高效的基因载体；以纳米载体为介导经门静脉注射的方法可使shRNA质粒在体内肝脏获得高效转染。
第二部分纳米载体介导沉默基因CⅡTA和MyD88表达的体内研究
目的：观察RNA干扰对免疫识别相关基因CⅡTA、MHC-Ⅱ和MyD88表达的抑制效果。方法：设置生理盐水对照组、纳米载体组、纳米载体pHK-shRNA组和纳米载体pC Ⅱ TA-shRNA组、纳米载体pMyD88-shRNA组、纳米载体pCⅡTA-pMyD88-shRNA组三个干预组,通过门静脉注射方法体内转染大鼠肝脏,转染后第三天取肝脏,以荧光定量PCR(?)western blot分别检测肝脏转染后CⅡTA、MHC-Ⅱ和MyD88基因mRNA和蛋白水平的表达变化。结果：荧光实时定量PCR和western blot检测显示纳米载体pC Ⅱ TA-shRNA组和纳米载体pCⅡTA-pMyD88-shRNA组CⅡTA和MHC Ⅱ基因mRNA和蛋白表达均较生理盐水组、纳米载体组和纳米载体pHK-shRNA组显著降低(P<0.01)；纳米载体pMyD88-shRNA组和纳米载体pC Ⅱ TA-pMyD88-shRNA组MyD88基因]mnRNA和蛋白表达较生理盐水组、纳米载体组和纳米载体pHK-shRNA组也有显著降低(P<0.01)；而纳米载体组、纳米载体pHK-shRNA组与生理盐水组之间CⅡTA、MHCⅡ和MyD88基因无论mRNA还是蛋白表达均无显著性差异(P>0.05)。结论：以纳米载体(HGPAEs)为介导经门静脉注射的方法,应用针对CⅡTA和MyD88的shRNA质粒转染大鼠肝脏,可显著抑制肝脏CⅡTA、MHC-Ⅱ和MyD88基因表达。
第三部分干预供体移植物抑制大鼠肝移植排斥反应的研究
目的：观察抑制供体肝脏CⅡTA和MyD88基因的表达对高应答大鼠原位肝移植模型移植排斥反应的影响,探讨其抗排斥机制。方法：建立高应答大鼠原位肝移植模型；设置生理盐水组、纳米载体组、pHK-shRNA纳米载体组、纳米载体pC Ⅱ TA-shRNA组、纳米载体pMyD88-shRNA组和纳米载体pCⅡTA-pMyD88-shRNA组,各组采用经门静脉注射的方法干预供体大鼠肝脏,干预后3天取肝脏进行肝移植,每组各12只大鼠,于移植术后第5天随机选取6只大鼠取静脉血和移植肝脏,病理切片确定排斥反应分级,分别采用荧光定量PCR和western blot检测肝中CⅡTA、MHC-Ⅱ和MyD88基因在mRNA和蛋白水平的表达变化,流式细胞术检测血中CD4/CD8细胞比例,ELISA去检测血清IL-2和IFN-γ浓度,并检测肝功能,其余6只用于观察存活期。结果：稳定建立高应答大鼠原位肝移植模型；与生理盐水组、纳米载体组和纳米载体pHK-shRNA组.相比,纳米载体pCⅡTA-shRNA组、纳米载体pMyD88-shRNA组和纳米载体pC Ⅱ TA-pMyD88-shRNA组大鼠存活时间明显延长(中位生存期16天、14天和21天vs10天、9天和8天,P<0.01),排斥反应病理分级明显降低(P
Objective:To prepare the nanometer vector HGPAEs and observe its safety and efficiency in vivo. Methods:The nanometer vector HGPAEs was prepared and tested. Normal saline group, nanometer group and nanometer vector pHK-shRNA control group were established for comparison and direct portal vein injection was performed to transfect liver. Liver specimens and blood were taken on the first day and the third day after transfection. Spectrofluorometer was used to detect the green fluorescent protein (EGFP) intensity and biochemical indicators like ALT, AST, TBIL. Crea and Urea were also detected. Results:The nanometer vector HGPAEs was successfully prepared and it was proved to be a nice vector for gene transfection. The EGFP intensity in liver of nanometer vector pHK-shRNA control group was significantly higher than normal saline group and nanometer vector control group both on the two experimental time points (P<0.01),and it showed that the intensity on the third day was higher than that on the first day in the plasmid group(P<0.01). Compared with normal value, the ALT and AST of all the three groups significantly increased on the first day after transfection (P<0.01). while there were no significant difference among the three groups themselves (P>0.05), and all those biochemical indicators became normal on the third day after transfection (P>0.05). Conclusions.-The nanometer vector HGPAEs was easy to be prepared and it was a promising gene transfer vector because it was effective and safe. Highly efficient liver transfection can be achieved through direct portal vein injection of the nanometer vector and plasmid DNA.
Part Ⅱ In vivo study of inhibiting genes CⅡTA and MyD88with the help of nanometer vector
Objective:To observe the inhibition effects of RNAi on immune recognition genes CIITA, MHC-Ⅱand MyD88. Methods:Totally6groups, including normal saline control group, nanometer vector control group, nanometer vector pHK-shRNA control group and nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group, received liver transfection through portal vein injection. Real time PCR and western blot were performed to detect the expression of C ⅡTA, MHC-Ⅱ and MyD88in liver3days after transfection. Results:Realtime PCR and western blot showed that, compared with normal saline control group, nanometer vector control group and nanometer vector pHK-shRNA control group, the expression of C Ⅱ TA and MHC-Ⅱ were obviously inhibited both in nanometer vector pC Ⅱ TA-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group(P<0.01), and the expression of MyD88was also significantly inhibited in both nanometer vector pMyD88-shRNA group and nanometer vector pCⅡTA-pMyD88-shRNA group(P<0.01), while there was no obvious expression difference of C Ⅱ TA, MHC-Ⅱ and MyD88among the three control groups (P>0.05)). Conclusions:Highly efficient liver transfection can be achieved through direct portal vein injection of the nanometer vector and plasmid DNA. The expression of C Ⅱ TA, MHC-Ⅱ and MyD88in rat liver can be obviously inhibited by plasmids containing shRNAs targeting C Ⅱ TA and MyD88.
Part Ⅲ The study of reducing transplantation rejection of rat liver by interferencing donor liver
Objective:To observe the effect of inhibiting the expression of CⅡ TA and MyD88of graft on transplantation rejection in high responder model of rat orthotopic liver transplantation and investigate its anti-rejection mechanism. Methods:The high responder model of rat orthotopic liver transplantation was established. There were7groups:normal saline control group, nanometer vector control group, nanometer vector pHK-shRNA control group, nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group, nanometer vector pC Ⅱ TA-pMyD88-shRNA group and CsA treating group. The donors in the first6groups received portal vein injection of normal saline or nanometer vector or nanometer vector and shRNA plasmid3days before transplantation.6recipients in each group were randomly chosen and sacrificed for their liver and blood as specimen5days after transplantation and the remaining6recipients were monitored for survival. The data of pathological rejection grading were collected by pathological examination, real-time PCR and western blot were used to test the mRNA and protein expression of CⅡTA, MHC-Ⅱ and MyD88in graft respectively, Flow Cytometry was used to test the ratio of CD4/CD8in blood, ELISA was used to observe the concentration of IL-2and IFN-y in serum, and liver function was also detected. Results:The high responder model of rat orthotopic liver transplantation was stably established. Compared to normal saline control group, nanometer vector control group and nanometer pHK-shRNA control group, the survival time of nanometer vector pC Ⅱ TA-shRNA group, nanometer vector pMyD88-shRNA group and nanometer vector pC Ⅱ TA-pMyD88-shRNA group extended significantly (median survival time16days,14days and21days vs1Odays,9days and8days, P<0.01), pathological rejection grading significantly depressed(P<0.01), the expressions of CⅡTA, MHC-Ⅱ and MyD88decreased significantly both on mRNA and protein level(P<0.01), the ratio of CD4/CD8in blood decreased obviously, the concentration of IL-2and IFN-γ in serum as well as liver function decreased significantly(P<0.01). Conclusion:High responder model of rat orthotopic liver transplantation is an ideal animal modelfor the study of liver transplantation rejection. Acute rejection reaction can be significantly relieved and survival time is extended by pretreatment of graft with portal vein injection of nanometer and shRNA plasmid targeting C Ⅱ TA and MyD88genes, which shows new way for both transplantation rejection research and clinical therapy.
引文
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