慢病毒介导的ICAM-1基因沉默治疗大鼠肾移植模型急性排斥反应的实验研究
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摘要
第一部分:大鼠同种异体肾移植模型的建立
目的:建立一种稳定、可靠、实用的大鼠同种异体肾移植急性排斥反应模型。
方法:1.采用移植肾置于左侧,供肾原位低温灌洗;移植肾带主动脉瓣与受体腹主动脉端-侧吻合;供体左肾静脉连其上方下腔静脉断端与受体下腔静脉端-侧吻合;供体输尿管带膀胱瓣与受体膀胱吻合。2.技术熟练后,行Wistar→SD大鼠肾移植,随机分为2组(每组12只):A组(排斥组),不作任何治疗;B组(CsA治疗组),术后使用CsA 10d。两组均行病理检查和观察生存期。
结果:1.经过3个月的练习,建立了比较稳定的大鼠同种异体肾移植模型。手术成功率可达到90%。2. A组平均存活7.33d;B组平均存活21.2d。术后7天病理检查示A组出现明显的急性排斥反应。
结论:此模型较容易掌握,除常规显微外科器械外不需要特殊的器械或设备。
第二部分:携带大鼠ICAM-1基因RNA干扰慢病毒载体的构建、体外鉴定与初步体内实验
目的:1.构建携带大鼠ICAM-1 RNA干扰的重组慢病毒。2.筛选出基因抑制效率最高的重组慢病毒。3.研究慢病毒载体体内转染主要脏器的有效性。
方法:1.根据基因序列,设计并合成针对4个靶点的寡核苷酸,制备双链DNA oligo;Hpa I和Xho I酶切pGCL-GFP载体以使其线性化,将其与双链DNA oligo在DNA连接酶作用下进行连接反应,将连接产物转化DH5α大肠杆菌感受态细胞,PCR筛选获得阳性克隆并进行基因测序。2.将重组载体与病毒包装质粒共转染人胚肾293 T细胞,获得的病毒颗粒经浓缩后测定滴度。3.通过重组慢病毒体外转染NRK细胞,以RT-PCR和Western Blot法筛选出基因抑制效率最高的重组慢病毒,并将其再次扩增、浓缩后测定滴度。4. SD大鼠静脉注射不同浓度重组慢病毒,分别于96小时、25天后检测报告基因表达情况。
结果:1.经过酶切、连接、转化后获得阳性克隆;基因测序结果完全正确。2.获得的针对4个靶点的重组慢病毒,经RT-PCR和Western Blot法证实,3#病毒在MOI=50时,基因抑制率即达到88.4%。3.大鼠体内实验表明,20×108 TU重组慢病毒可有效转染各主要脏器,转染25d后大鼠肾组织仍在不断表达报告基因。
结论:1.成功构建了含有GFP报告基因的大鼠ICAM-1 RNA干扰慢病毒载体。2.体外实验证实了该慢病毒载体能高效转导NRK细胞,并能有效阻断目的基因的表达。3.体内实验初步确定了该慢病毒载体的有效性。
第三部分:慢病毒介导的ICAM-1基因沉默治疗大鼠肾移植模型急性排斥反应
目的:1.研究携带大鼠ICAM-1 RNA干扰的重组慢病毒抑制移植肾ICAM-1基因表达的作用。2.探讨慢病毒介导的ICAM-1基因沉默防治大鼠肾移植模型急性排斥反应的作用效果和机理。3.初步探讨慢病毒载体结合RNA干扰应用于同种异体移植排斥的效果和前景。
方法:1.供体为Wistar大鼠、受体为SD大鼠肾移植,随机分为4组(每组12只):a组(同系对照组);b组(排斥组),不作任何治疗;c组(空白对照病毒组):供体术前96小时尾静脉输注空白对照病毒20×108 TU;d组(治疗组):供体术前96小时尾静脉输注rICAM重组慢病毒20×108 TU。2.肾移植术后观察生存期,并抽取外周血,检测肾功能,ELISA法检测血清IL-2、ICAM-1的浓度。3.肾移植术后7天取移植肾,RT-PCR和Western Blot法检测移植肾ICAM-1的表达;HE染色观察病理变化。
结果:1.肾移植术后治疗组生存期达23.8天,与b、c两组(仅为7.3、7.0天)相比有统计学差异。2.肾移植术后治疗组血清Cr、IL-2、ICAM-1的浓度与同系对照组相比无显著差别,而与b、c两组差别巨大。3.肾移植术后7天,治疗组移植肾ICAM-1表达明显被抑制。HE染色提示移植肾Banff 0~ⅠA级,而b、c组移植肾BanffⅡB-ⅢA级。
结论:1.携带ICAM-1 RNA干扰的重组慢病毒可以有效地、特异性地抑制移植肾ICAM基因的表达。2.被植入经rICAM重组慢病毒转染的供肾后,受体的生存期明显延长。3.慢病毒介导的ICAM-1基因沉默治疗大鼠肾移植模型急性排斥反应效果良好,具有潜在的应用价值。
Part one The establishment of a renal allogrft model in rats
Objective: To establish an acute renal allograft rejection model in rats.
Methods: Rat renal transplantations were performed with hypothermia infusion conducting at dystopy, donor kidney grafted at the left side, end-side anastomosis of the donor left renal artery valve to recipient abdominal aorta, end-side anastomosis of the donor left vena cava to the recipient vena cava. To suture the donor ureter with ureterocystic flap to the recipient’s bladder. The rats were randomly divided into 2 groups, Wistar rats were served as donors and SD rats as recipients. Group A without any treatment , whereas Group B were injected CsA 6mg/kg/d×10d. . The pathological changes of the grafts were observed 7 days after transplantation. Meanwhile, recorded the survival time.
Results: After three months training, the rate of succeeding reached 90%. Pathological results showed that severity of acute reject reaction after 7 days was gradeⅡB-Ⅲin Group A. At the same time, survival time of rats exceeded 15 days in Group B, and was 7.3 days in Group A. Conclusion: A stable and reliable model of renal allograft in rats was established with high acute rejection rate.
Part two Construction and identification of the lentiviral RNAi vector of rat ICAM-1 gene in vitro and in vivo
Objective: To construct the recombinated lentivirus which carrying siRNA of rat ICAM-1 gene. To identificat the most effective lentivirus.Study the efficacy of lentivirus transfecting animal organs in vivo.
Methods: Four specific target sequences were selected according to rat ICAM-1 mRNA sequence, and non-specific served as control group. The DNA oligonucleotide were cut with Hpa I and Xho I, then subcloned it into the plasmid pGCL-GFP which was also cut with Hpa I and Xho I ,ligated by DNA ligase,and the acquired recombinants were subsequently transfected into E coli strain DH53 for preparing recombinant.The polymerase chain reaction(PCR) was used to determine whether there were integration of needed DNA oligonucleotide and examined the sequence of the plasmid.This recombinanted plasmid was cotransfected along with Helper 1.0 and Helper 2.0 into HEK293T to package lentivirus particles. According to the GFP expression, the functional titer of recombinated lentivirus is determined by FCM after transduction into HEK293T cells.Then Compare with the RNAi effect of four specific target sequences inhibited the expressing of ICAM-1 in NRK cells by Real-time RT-PCR and Western Blot.The best lentivirus was amplified and concentrated,then determined the functional titer again. SD rats were injected lentivirus by vena .Examine the expression of GFP 96 hours and 25 days later.
Results: It is confirmed by digestion and sequencing that ICAM-1 shRNA expression structure is correctly cloned to pGCL-GFP. After cotransfection, lentiviral vector can be packaged in HEK293T cells.The No.3 lentivirus was the most effective one.When MOI=50,the rate of No.3 lentivirus inhibiting the gene expression was 88.4% in vitro.In vivo,injecting 20×108 TU lentivirus by vena could effective transfect to the most organs of rats.The GFP gene could keep expression over 25 days. Conclusion:Successfully constructed the recombinated lentivirus carrying siRNA of rat ICAM-1 gene .
Part three Gene therapy of the acute rejection of renal allografts with Lentiviral ector-mediated down-regulation of ICAM-1 in rats
Objective:To study the efficiency of rICAM-lentivirus in prevent renal allografts acute rejection in rats.
Methods: The rats were randomly divided into 4 groups.The Group a(syngraft), SD to SD rats; Group b to d, Wistar rats to SD rats. Group a and Group b without any treatment , whereas donors were injected 20×108 TU lentivirus 4 days before transplant operation at Group c and d. While Group c injected with non-silence cortrol lentivirus differed from Group d injected with rICAM lentivirus. After kidney transplantation, the peripheral blood were obtained to exam the kidney function .At the same time, the level of IL-2 and sICAM were examed using enzyme-linked immunosorbent assay(ELISA). The pathological character and ICAM-1 mRNA of the grafts were observed after transplantation 7 days. Meanwhile, the survival time was recorded.
Results: The levels of creatinine of serum were significantly higher in Group b and c than in Group a and d in 7 days post transplantation. Pathological results showed that severity of acute reject reaction after 7 days was gradeⅡB-Ⅲin Group b and Group c, grade 0-ⅠA in Group a and Group d. The copy of ICAM-1 mRNA in allografts was remarkably high in Group b and c. The results of ELISA showed that there were higher level of IL-2 and sICAM-1 in Group b and Group c,meanwhile survival time of rats exceeded 100 days in Group a, and was 7.3 days in Group b, 7.0 days in Group c, 23.8 days in Group d.
Conclusion: Lentiviral vector-mediated down-regulation of intercellular adhesion molecule-1 is a effective method to therapy the acute rejection of renal allografts with promise well.
目的:建立一种稳定、可靠、实用的大鼠同种异体肾移植急性排斥反应模型。
方法:1.采用移植肾置于左侧,供肾原位低温灌洗;移植肾带主动脉瓣与受体腹主动脉端-侧吻合;供体左肾静脉连其上方下腔静脉断端与受体下腔静脉端-侧吻合;供体输尿管带膀胱瓣与受体膀胱吻合。2.技术熟练后,行Wistar→SD大鼠肾移植,随机分为2组(每组12只):A组(排斥组),不作任何治疗;B组(CsA治疗组),术后使用CsA 10d。两组均行病理检查和观察生存期。
结果:1.经过3个月的练习,建立了比较稳定的大鼠同种异体肾移植模型。手术成功率可达到90%。2. A组平均存活7.33d;B组平均存活21.2d。术后7天病理检查示A组出现明显的急性排斥反应。
结论:此模型较容易掌握,除常规显微外科器械外不需要特殊的器械或设备。
第二部分:携带大鼠ICAM-1基因RNA干扰慢病毒载体的构建、体外鉴定与初步体内实验
目的:1.构建携带大鼠ICAM-1 RNA干扰的重组慢病毒。2.筛选出基因抑制效率最高的重组慢病毒。3.研究慢病毒载体体内转染主要脏器的有效性。
方法:1.根据基因序列,设计并合成针对4个靶点的寡核苷酸,制备双链DNA oligo;Hpa I和Xho I酶切pGCL-GFP载体以使其线性化,将其与双链DNA oligo在DNA连接酶作用下进行连接反应,将连接产物转化DH5α大肠杆菌感受态细胞,PCR筛选获得阳性克隆并进行基因测序。2.将重组载体与病毒包装质粒共转染人胚肾293 T细胞,获得的病毒颗粒经浓缩后测定滴度。3.通过重组慢病毒体外转染NRK细胞,以RT-PCR和Western Blot法筛选出基因抑制效率最高的重组慢病毒,并将其再次扩增、浓缩后测定滴度。4. SD大鼠静脉注射不同浓度重组慢病毒,分别于96小时、25天后检测报告基因表达情况。
结果:1.经过酶切、连接、转化后获得阳性克隆;基因测序结果完全正确。2.获得的针对4个靶点的重组慢病毒,经RT-PCR和Western Blot法证实,3#病毒在MOI=50时,基因抑制率即达到88.4%。3.大鼠体内实验表明,20×108 TU重组慢病毒可有效转染各主要脏器,转染25d后大鼠肾组织仍在不断表达报告基因。
结论:1.成功构建了含有GFP报告基因的大鼠ICAM-1 RNA干扰慢病毒载体。2.体外实验证实了该慢病毒载体能高效转导NRK细胞,并能有效阻断目的基因的表达。3.体内实验初步确定了该慢病毒载体的有效性。
第三部分:慢病毒介导的ICAM-1基因沉默治疗大鼠肾移植模型急性排斥反应
目的:1.研究携带大鼠ICAM-1 RNA干扰的重组慢病毒抑制移植肾ICAM-1基因表达的作用。2.探讨慢病毒介导的ICAM-1基因沉默防治大鼠肾移植模型急性排斥反应的作用效果和机理。3.初步探讨慢病毒载体结合RNA干扰应用于同种异体移植排斥的效果和前景。
方法:1.供体为Wistar大鼠、受体为SD大鼠肾移植,随机分为4组(每组12只):a组(同系对照组);b组(排斥组),不作任何治疗;c组(空白对照病毒组):供体术前96小时尾静脉输注空白对照病毒20×108 TU;d组(治疗组):供体术前96小时尾静脉输注rICAM重组慢病毒20×108 TU。2.肾移植术后观察生存期,并抽取外周血,检测肾功能,ELISA法检测血清IL-2、ICAM-1的浓度。3.肾移植术后7天取移植肾,RT-PCR和Western Blot法检测移植肾ICAM-1的表达;HE染色观察病理变化。
结果:1.肾移植术后治疗组生存期达23.8天,与b、c两组(仅为7.3、7.0天)相比有统计学差异。2.肾移植术后治疗组血清Cr、IL-2、ICAM-1的浓度与同系对照组相比无显著差别,而与b、c两组差别巨大。3.肾移植术后7天,治疗组移植肾ICAM-1表达明显被抑制。HE染色提示移植肾Banff 0~ⅠA级,而b、c组移植肾BanffⅡB-ⅢA级。
结论:1.携带ICAM-1 RNA干扰的重组慢病毒可以有效地、特异性地抑制移植肾ICAM基因的表达。2.被植入经rICAM重组慢病毒转染的供肾后,受体的生存期明显延长。3.慢病毒介导的ICAM-1基因沉默治疗大鼠肾移植模型急性排斥反应效果良好,具有潜在的应用价值。
Part one The establishment of a renal allogrft model in rats
Objective: To establish an acute renal allograft rejection model in rats.
Methods: Rat renal transplantations were performed with hypothermia infusion conducting at dystopy, donor kidney grafted at the left side, end-side anastomosis of the donor left renal artery valve to recipient abdominal aorta, end-side anastomosis of the donor left vena cava to the recipient vena cava. To suture the donor ureter with ureterocystic flap to the recipient’s bladder. The rats were randomly divided into 2 groups, Wistar rats were served as donors and SD rats as recipients. Group A without any treatment , whereas Group B were injected CsA 6mg/kg/d×10d. . The pathological changes of the grafts were observed 7 days after transplantation. Meanwhile, recorded the survival time.
Results: After three months training, the rate of succeeding reached 90%. Pathological results showed that severity of acute reject reaction after 7 days was gradeⅡB-Ⅲin Group A. At the same time, survival time of rats exceeded 15 days in Group B, and was 7.3 days in Group A. Conclusion: A stable and reliable model of renal allograft in rats was established with high acute rejection rate.
Part two Construction and identification of the lentiviral RNAi vector of rat ICAM-1 gene in vitro and in vivo
Objective: To construct the recombinated lentivirus which carrying siRNA of rat ICAM-1 gene. To identificat the most effective lentivirus.Study the efficacy of lentivirus transfecting animal organs in vivo.
Methods: Four specific target sequences were selected according to rat ICAM-1 mRNA sequence, and non-specific served as control group. The DNA oligonucleotide were cut with Hpa I and Xho I, then subcloned it into the plasmid pGCL-GFP which was also cut with Hpa I and Xho I ,ligated by DNA ligase,and the acquired recombinants were subsequently transfected into E coli strain DH53 for preparing recombinant.The polymerase chain reaction(PCR) was used to determine whether there were integration of needed DNA oligonucleotide and examined the sequence of the plasmid.This recombinanted plasmid was cotransfected along with Helper 1.0 and Helper 2.0 into HEK293T to package lentivirus particles. According to the GFP expression, the functional titer of recombinated lentivirus is determined by FCM after transduction into HEK293T cells.Then Compare with the RNAi effect of four specific target sequences inhibited the expressing of ICAM-1 in NRK cells by Real-time RT-PCR and Western Blot.The best lentivirus was amplified and concentrated,then determined the functional titer again. SD rats were injected lentivirus by vena .Examine the expression of GFP 96 hours and 25 days later.
Results: It is confirmed by digestion and sequencing that ICAM-1 shRNA expression structure is correctly cloned to pGCL-GFP. After cotransfection, lentiviral vector can be packaged in HEK293T cells.The No.3 lentivirus was the most effective one.When MOI=50,the rate of No.3 lentivirus inhibiting the gene expression was 88.4% in vitro.In vivo,injecting 20×108 TU lentivirus by vena could effective transfect to the most organs of rats.The GFP gene could keep expression over 25 days. Conclusion:Successfully constructed the recombinated lentivirus carrying siRNA of rat ICAM-1 gene .
Part three Gene therapy of the acute rejection of renal allografts with Lentiviral ector-mediated down-regulation of ICAM-1 in rats
Objective:To study the efficiency of rICAM-lentivirus in prevent renal allografts acute rejection in rats.
Methods: The rats were randomly divided into 4 groups.The Group a(syngraft), SD to SD rats; Group b to d, Wistar rats to SD rats. Group a and Group b without any treatment , whereas donors were injected 20×108 TU lentivirus 4 days before transplant operation at Group c and d. While Group c injected with non-silence cortrol lentivirus differed from Group d injected with rICAM lentivirus. After kidney transplantation, the peripheral blood were obtained to exam the kidney function .At the same time, the level of IL-2 and sICAM were examed using enzyme-linked immunosorbent assay(ELISA). The pathological character and ICAM-1 mRNA of the grafts were observed after transplantation 7 days. Meanwhile, the survival time was recorded.
Results: The levels of creatinine of serum were significantly higher in Group b and c than in Group a and d in 7 days post transplantation. Pathological results showed that severity of acute reject reaction after 7 days was gradeⅡB-Ⅲin Group b and Group c, grade 0-ⅠA in Group a and Group d. The copy of ICAM-1 mRNA in allografts was remarkably high in Group b and c. The results of ELISA showed that there were higher level of IL-2 and sICAM-1 in Group b and Group c,meanwhile survival time of rats exceeded 100 days in Group a, and was 7.3 days in Group b, 7.0 days in Group c, 23.8 days in Group d.
Conclusion: Lentiviral vector-mediated down-regulation of intercellular adhesion molecule-1 is a effective method to therapy the acute rejection of renal allografts with promise well.
引文
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12 Ketting R F,Fischer S E,Berivsteiiv E,et al.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegarts.Genes Dev,2001,15(20):2654-2659.
13 Martinez J.Tuschl T.RISC is a 5' phosphomonoester producing RNA endonuclease .Genes Dev,2004, l8(9):975-980.
14 Tusterman M,Plasterk R H.Dicers at RISC;the mechanism of RNAi.Cell,2004, ll7(1):1-3
15 Zeng Y, Cullen B R.RNA interference in human cells is restricted to the cytoplasm.RNA,2002,8(7): 855-860.
16 Kawaski H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucleic Acids Res,2003,3l(2):700-707.
17 Irie N,Sakai N,Ueyama T,et al.Subtype and species specific knockdown of PKC using short interfering RNA. Biochem Biophys Res Commun, 2002 ,298(5):738-743.
18 M ah C,Byme BJ,Floote TR.Virus-based gene deliver systems.Clin Phamacokinet 2002,41:901-911.
19 Naldini L,BlomerU,Gallay P,et al.In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.Science,1996,272(5259):263-267.
20 Kafri T,Van Praag H,Ouyang L,et al.A packaging cell line for Lentivirus vectors.J Virol,1999,73:576.
21 Buchschacher GL Jr,Wong-Staal F.Development of lentiviral vectors for human diease.Blood,2000,95(8):2499-2504
22 Rothlein R. Dustin ML,Marlin SD,Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of Immunology,1986 ,137(4):1270-4.
23 Voraberger G,Schafer R,Stratowa C. Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region Induction by cytokines and phorbol ester. Journal of Immunology,1991,147(8):2777-86.
24迟伟玲。慢病毒介导的鸟氨酸脱梭酶基因沉默抑制结直肠癌细胞生长的体外和体内研究。2006,山东大学博士论文。
25 Abbas-Terki T. Blanco-Bose W. Deglon N,et al. Lentiviral-mediated RNA interference. Human Gene Therapy.2002, 13(18):2197-201
1. Crespo M,et al.Acute humoral rejection in renal allograft recipients: Incidence, serology and clinical characteristics. Transplantation ,2001; 71:752-658
2. Hariharan S.Long-term kidney transplant survival. Am J Kidney Dis ,2001;38(6):S44-50
3. Lechler R, Ng WF, Steinman RM.Dendritic cells in transplantation: friend or foe?Immunity ,2001;14(4):357-68
4. Femandes JR,Duvivier-Kali V F,Keegan M,et al.Transplantation of islets transduced with CTLA4-Ig and TGFb using adenovirus and lentivirus vectors. Transplant Immunology ,2004;13: 191一200
5. Adams AB, Shirasugi N, Strobert EA, et al. Combined blockade of the CD40 and CD28 pathways synergizes to promote islet allograft survival in a non-human primate model.AmJ Transplant,2003;3:317
6. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies in renal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
7. Cosimiab. In vivo effects of monoclonal antibody to ICAM-1(CD54) in nonhuman primates with renal allografts. J Immunol ,1990;144(12) :4604– 4612
8. Degawa H ,Watanabe K, Beck Y,et al. Effect of anti-ICAM-1and anti-LFA-1 antibodies on rat liver transplantation.Surg Today ,1995;25(5) :474– 476
9. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies inrenal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
10. Katz SM, Browne B, Phan T,et al. Efficacy of ICAM-1 antisense oligonucleotide in pancreatic islet transplantation. Transplant Proc,1995;27(6):3214
11. Stepkowski SM, Wang ME, Condon TP,et al. Protection against allograft rejection with intercellular adhesion molecule-1 antisense oligodeoxynucleotides. Transplantation,1998;27;66(6):699-707
12. Zhang QW,Kish DD,Fairchild RL. Absence of allograft ICAM-1 attenuates alloantigen-specific T cell priming, but not primed T cell trafficking into the graft, to mediate acute rejection. J of Immunology,2003;170(11):5530-7
13. Lacha J. Bushell A. Smetana K,et al. Intercellular cell adhesion molecule-1 and selectin ligands in acute cardiac allograft rejection: a study on gene-deficient mouse models. J of Leukocyte Biology, 2002;71(2):311-8
14. Far, Rosel Kretschmer-Kazemi; Sczakiel, Georg. The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides. Nucleic Acids Research,2003;31(15):4417-4424
15. Abbas-Terki T. Blanco-Bose W. Deglon N. Lentiviral-mediated RNA interference. Human Gene Therapy, 2002;13(18):2197-201
16. Rubinson DA. Dillon CP. Kwiatkowski AV.et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nature Genetics,2003;33(3):401-6
17. An DS. Xie Y. Mao SH.et al. Efficient lentiviral vectors for short hairpin RNA delivery into human cells. Human Gene Therapy,2003;14(12):1207-12
18. Wiznerowicz M. Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. Journal of Virology,2003,77(16):8957-61
19. Hombach A, Heuser C, Abken H. Simultaneous targeting of IL2 and IL 12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis.Int J Cancer,2005;115(2):241-247.
20. Rossini AA,Greiner DL,Mordes JP.Induction of immunologic tolerance for transplantation. Physio Rev,1999,79:99-141.
21. Kutukculer N, Shenton BK, Clark K,et al. Renal allograft rejection: the temporal relationship and predictive value of plasma TNF (alpha and beta), IFN-gamma and soluble ICAM-1. Transpl Int. 1995;8(1):45-50.
22. Ninovao. Hepatic allograft rejection is associated with increased levels of soluble intercellular adhesion molecule-1.Liver Transpl Surg. 1995;1(5):290-295.
23. Racusen L,et al.The Banff 97 working classification of renal allograft pathology.Kidney Int,1999,55:713-723.
1. Rothlein R. Dustin ML. Marlin SD. Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of Immunology. 1986 ,137(4):1270-4.
2. Kevil CG,Pruitt H,Kavanagh TJ, et al.Regulation of endothelial glutathione by ICAM-1:implications for inflammation. FASEB J.2004 Aug;18 (11):1321一1323.
3. Van de Stolpe A,Van der Saag PT. Intercellular adhesion molecule-1. J Mol Med .1996; 74:13-33.
4. Tamura DY,Moore EE,Johnson J,et al .p38 mitogen-activated prot ein kinase inhibition attenuates intercellular adhesion molecule-1 upregulation on human pulmonary microvascular endothelial cells. Surgery .1998; 124:403-407.
5.白寒,蒋立城.ICAM-1,LFA一与肾移植排异反应的诊断和治疗.国外医学·泌尿系统分册.2000 ; 20 (1) : 28-29.
6. RIBEIRON DS,DAVID VETO E, CASTRO MC, et al. Contribution of th e expression of ICAM- 1,HLA-DR and IL-2R to the diagnosis of acute refection in renal allograft aspirative cytology.Transpl Int.1998;11(1):S19-25
7. Thervet E,Patey N,Legendre C,et al. Comprehensive examination of gene expression associated with long-term stable graft acceptance by renal transplant recipients. Clin Transplant.2004:18(1):70-78.
8. [7]Berney J,Thierry J, Pileggi M, et al. The effect of simultaneous CD54 and LFA-1 blockade on the survival of allogeneic grafts in non obese diabeticmice.transplantation. 2003; 76(12):1669-1674.
9.娄诚.粘附分子ICAM-1在移植免疫中的作用.Continuing Medical Education. 2003: 17 (3):32-35.
10. Hombach A, Heuser C, Abken H. Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis.Int J Cancer.2005;115(2):241-247.
11. GEARINGAJH} NEWMAN W. Circulating adhesion molecules in disease. Immunol Today.1993; 14:506-512.
12. NINOVA D. Hepatic allograft rejection is associated with increased levels of soluble intercellular adhesion molecule-1.Liver Transpl Surg. 1995;1(5):290-295.
13. KANAGWAK SCKI T, NISHIGAKI F. Measurement of soluble ICAM-1 after renal transplantation[J].Transplant Proc.1994;25 (4):2103-2105.
14. Teppo AM, von Willebrand E, Honkanen E, et al.Soluble intercellular adhesion molecule-1 (sICAM-1) after kidney transplantation:the origin and role of urinary sICAM-l.Transplantation.2001;71(8):1113-1119.
15. Witkowska AM, Borawska MH.Soluble intercellular adhesion molecule-1 (sICAM-1):an overview .Eur Cytokine Netw.2004;15 (2):91-98.
16. COSIMI AB. In vivo effects of monoclonal antibody to ICAM- 1(CD54)in nonhuman primates with renal allografts.J Immunol.1990;144(12): 4604-4612.
17. Nozawa M, Otsu I, Kobayashi H,et al. New immunosuppression with monoclonal antibody to intracellular adhesion molecule 1 (ICAM-1) in rat organ transplantation. Transpl Int. 1992;S521-3.
18. Isobe M, Yagita H, Okumura K, et al. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science. 1992; 28;255(5048):1125-7
19. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies in renal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
20. Stepkowski SM, Tu Y, Condon TP,et al. Blocking of heart allograft rejection by intercellular adhesion molecule-1 antisense oligonucleotides alone or in combination with other immunosuppressive modalities. J Immunol. 1994 ;153(11):5336-46
21. Obika S,Hemamayi R,Masuda T, et al. Inhibition of ICAM-1 gene expression by antisense 2',4',-BNA oligonucleotides.Nucleic Acids Res Suppl.2001;(1):145-146.
22. Cheng QL,Chen XM, Li F,et al .Effects of ICAM-1 antisense oligonucleotide on the tubulointerstitium in mice with unilateral uretera obstruction.Kidney Int.2000; 57(1):183-190.
23. Stekowski SM. Development of antisense oligodeoxy nucleotides for transplantation.Curr Opin Mol Ther .2000: 2(3):304一317.
24. Salmela K. Wramner L. Ekberg H,et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation, 1999;67(5):729-36
25. Katz SM, Browne B, Phan T,et al. Efficacy of ICAM-1 antisense oligonucleotide in pancreatic islet transplantation. Transplant Proc,1995;27(6):3214
26. Maldonado M, Baybis M, Newman D,et al.Expression of ICAM-1,TNF-alpha, NF kappa B and MAP kinase in tubers of the tuberous sclerosis complex.Neurobiol Dis.2003:14 (2):279-290.
27. Audette M, Larouche L, Lussier I,et a1. Stimulation of the ICAM-1 gene transcription by the peroxovanadium compound [bpV(Pic)]involves STAT-1 but not NF-kappa B activation in 293 ce1ls.Eur J Biochem.2001:268 (6):1828-1836.
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13.冯嘉瑜,张艮甫.改良的大鼠原位肾移植模型的建立.第三军医大学学报,2004,26:2264-2265.
14 . Bua mis TP . Microsurgical renal transplantation techniques in small animals.Invest Urol,1977,15:143-145.
15.钟晓祝,史伟.胸腺内注射供体MHC抗原诱导大鼠移植肾的长期存活.中华泌尿外科杂志,1997,18:472 473.
16. Racusen L,et al.The Banff 97 working classification of renal allograft pathology.Kidney Int,1999,55:713-723
1 Fire A,Xu S,Montgomery M K,et al.Potent and specific genetic interference by doble-stranded RNA in caenorhabditis elegans.Nature,1998,391(6669):806-811.
2 Tabara H, Grishok A, Mello CC.RNAi in C. elegans: soaking in the genome sequence. Science,1998, 282(5388): 430-431.
3 Rubinson DA. Dillon CP,Kwiatkowski AV et al.A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference.Nature Genetics,2003,33:401-406.
4 Leiden, J. M. Gene therapy-promise, pitfalls, and prognosis. N.Engl.J.Med,1995. 333: 871-873.
5 Amado,R.G.,and Chen,I.S.Y. The promise of gene therapy within reach? Science,1999,285:67-76.
6 Napoli C.Lemieux C.Jorgensen R.Introduction of a chimeric chalcone synthase gene into petunia results in reversible cosuppression of homologous genes in trans . Plant Cell, 1990. 2(4): 279-289.
7 Cogoni C, Homano N, Macino G. Suppression of gene expression by homologous transgenes . Antonie Van Leeuwenhoek, 1994,65(3): 205-209.
8 Brown S J.Mahaffey J P. Lorenzen M D, et al. Using RNAi to investigate orthologous homeotic gene function during development of distantly related insects.Evol Dev, 1999.1(1)11-15
9 Elbashir S M.Harborth J. Lendeckel W,et al. Duplexes of 2l-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature,2001, 411(6836):494-498.
10 Elbashir S M. Lendeckel W.Tushl.RNA interference is mediated by 2l-and 22-nucleotide RNAs.Genes Dev, 2001, 15(2): 188-200.
11 Berivstein E, Caudy A A. Hammond S M, et al. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature, 2001, 409 (6818):363-366.
12 Ketting R F,Fischer S E,Berivsteiiv E,et al.Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegarts.Genes Dev,2001,15(20):2654-2659.
13 Martinez J.Tuschl T.RISC is a 5' phosphomonoester producing RNA endonuclease .Genes Dev,2004, l8(9):975-980.
14 Tusterman M,Plasterk R H.Dicers at RISC;the mechanism of RNAi.Cell,2004, ll7(1):1-3
15 Zeng Y, Cullen B R.RNA interference in human cells is restricted to the cytoplasm.RNA,2002,8(7): 855-860.
16 Kawaski H, Taira K. Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucleic Acids Res,2003,3l(2):700-707.
17 Irie N,Sakai N,Ueyama T,et al.Subtype and species specific knockdown of PKC using short interfering RNA. Biochem Biophys Res Commun, 2002 ,298(5):738-743.
18 M ah C,Byme BJ,Floote TR.Virus-based gene deliver systems.Clin Phamacokinet 2002,41:901-911.
19 Naldini L,BlomerU,Gallay P,et al.In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector.Science,1996,272(5259):263-267.
20 Kafri T,Van Praag H,Ouyang L,et al.A packaging cell line for Lentivirus vectors.J Virol,1999,73:576.
21 Buchschacher GL Jr,Wong-Staal F.Development of lentiviral vectors for human diease.Blood,2000,95(8):2499-2504
22 Rothlein R. Dustin ML,Marlin SD,Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of Immunology,1986 ,137(4):1270-4.
23 Voraberger G,Schafer R,Stratowa C. Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region Induction by cytokines and phorbol ester. Journal of Immunology,1991,147(8):2777-86.
24迟伟玲。慢病毒介导的鸟氨酸脱梭酶基因沉默抑制结直肠癌细胞生长的体外和体内研究。2006,山东大学博士论文。
25 Abbas-Terki T. Blanco-Bose W. Deglon N,et al. Lentiviral-mediated RNA interference. Human Gene Therapy.2002, 13(18):2197-201
1. Crespo M,et al.Acute humoral rejection in renal allograft recipients: Incidence, serology and clinical characteristics. Transplantation ,2001; 71:752-658
2. Hariharan S.Long-term kidney transplant survival. Am J Kidney Dis ,2001;38(6):S44-50
3. Lechler R, Ng WF, Steinman RM.Dendritic cells in transplantation: friend or foe?Immunity ,2001;14(4):357-68
4. Femandes JR,Duvivier-Kali V F,Keegan M,et al.Transplantation of islets transduced with CTLA4-Ig and TGFb using adenovirus and lentivirus vectors. Transplant Immunology ,2004;13: 191一200
5. Adams AB, Shirasugi N, Strobert EA, et al. Combined blockade of the CD40 and CD28 pathways synergizes to promote islet allograft survival in a non-human primate model.AmJ Transplant,2003;3:317
6. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies in renal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
7. Cosimiab. In vivo effects of monoclonal antibody to ICAM-1(CD54) in nonhuman primates with renal allografts. J Immunol ,1990;144(12) :4604– 4612
8. Degawa H ,Watanabe K, Beck Y,et al. Effect of anti-ICAM-1and anti-LFA-1 antibodies on rat liver transplantation.Surg Today ,1995;25(5) :474– 476
9. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies inrenal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
10. Katz SM, Browne B, Phan T,et al. Efficacy of ICAM-1 antisense oligonucleotide in pancreatic islet transplantation. Transplant Proc,1995;27(6):3214
11. Stepkowski SM, Wang ME, Condon TP,et al. Protection against allograft rejection with intercellular adhesion molecule-1 antisense oligodeoxynucleotides. Transplantation,1998;27;66(6):699-707
12. Zhang QW,Kish DD,Fairchild RL. Absence of allograft ICAM-1 attenuates alloantigen-specific T cell priming, but not primed T cell trafficking into the graft, to mediate acute rejection. J of Immunology,2003;170(11):5530-7
13. Lacha J. Bushell A. Smetana K,et al. Intercellular cell adhesion molecule-1 and selectin ligands in acute cardiac allograft rejection: a study on gene-deficient mouse models. J of Leukocyte Biology, 2002;71(2):311-8
14. Far, Rosel Kretschmer-Kazemi; Sczakiel, Georg. The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides. Nucleic Acids Research,2003;31(15):4417-4424
15. Abbas-Terki T. Blanco-Bose W. Deglon N. Lentiviral-mediated RNA interference. Human Gene Therapy, 2002;13(18):2197-201
16. Rubinson DA. Dillon CP. Kwiatkowski AV.et al. A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nature Genetics,2003;33(3):401-6
17. An DS. Xie Y. Mao SH.et al. Efficient lentiviral vectors for short hairpin RNA delivery into human cells. Human Gene Therapy,2003;14(12):1207-12
18. Wiznerowicz M. Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. Journal of Virology,2003,77(16):8957-61
19. Hombach A, Heuser C, Abken H. Simultaneous targeting of IL2 and IL 12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis.Int J Cancer,2005;115(2):241-247.
20. Rossini AA,Greiner DL,Mordes JP.Induction of immunologic tolerance for transplantation. Physio Rev,1999,79:99-141.
21. Kutukculer N, Shenton BK, Clark K,et al. Renal allograft rejection: the temporal relationship and predictive value of plasma TNF (alpha and beta), IFN-gamma and soluble ICAM-1. Transpl Int. 1995;8(1):45-50.
22. Ninovao. Hepatic allograft rejection is associated with increased levels of soluble intercellular adhesion molecule-1.Liver Transpl Surg. 1995;1(5):290-295.
23. Racusen L,et al.The Banff 97 working classification of renal allograft pathology.Kidney Int,1999,55:713-723.
1. Rothlein R. Dustin ML. Marlin SD. Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. Journal of Immunology. 1986 ,137(4):1270-4.
2. Kevil CG,Pruitt H,Kavanagh TJ, et al.Regulation of endothelial glutathione by ICAM-1:implications for inflammation. FASEB J.2004 Aug;18 (11):1321一1323.
3. Van de Stolpe A,Van der Saag PT. Intercellular adhesion molecule-1. J Mol Med .1996; 74:13-33.
4. Tamura DY,Moore EE,Johnson J,et al .p38 mitogen-activated prot ein kinase inhibition attenuates intercellular adhesion molecule-1 upregulation on human pulmonary microvascular endothelial cells. Surgery .1998; 124:403-407.
5.白寒,蒋立城.ICAM-1,LFA一与肾移植排异反应的诊断和治疗.国外医学·泌尿系统分册.2000 ; 20 (1) : 28-29.
6. RIBEIRON DS,DAVID VETO E, CASTRO MC, et al. Contribution of th e expression of ICAM- 1,HLA-DR and IL-2R to the diagnosis of acute refection in renal allograft aspirative cytology.Transpl Int.1998;11(1):S19-25
7. Thervet E,Patey N,Legendre C,et al. Comprehensive examination of gene expression associated with long-term stable graft acceptance by renal transplant recipients. Clin Transplant.2004:18(1):70-78.
8. [7]Berney J,Thierry J, Pileggi M, et al. The effect of simultaneous CD54 and LFA-1 blockade on the survival of allogeneic grafts in non obese diabeticmice.transplantation. 2003; 76(12):1669-1674.
9.娄诚.粘附分子ICAM-1在移植免疫中的作用.Continuing Medical Education. 2003: 17 (3):32-35.
10. Hombach A, Heuser C, Abken H. Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis.Int J Cancer.2005;115(2):241-247.
11. GEARINGAJH} NEWMAN W. Circulating adhesion molecules in disease. Immunol Today.1993; 14:506-512.
12. NINOVA D. Hepatic allograft rejection is associated with increased levels of soluble intercellular adhesion molecule-1.Liver Transpl Surg. 1995;1(5):290-295.
13. KANAGWAK SCKI T, NISHIGAKI F. Measurement of soluble ICAM-1 after renal transplantation[J].Transplant Proc.1994;25 (4):2103-2105.
14. Teppo AM, von Willebrand E, Honkanen E, et al.Soluble intercellular adhesion molecule-1 (sICAM-1) after kidney transplantation:the origin and role of urinary sICAM-l.Transplantation.2001;71(8):1113-1119.
15. Witkowska AM, Borawska MH.Soluble intercellular adhesion molecule-1 (sICAM-1):an overview .Eur Cytokine Netw.2004;15 (2):91-98.
16. COSIMI AB. In vivo effects of monoclonal antibody to ICAM- 1(CD54)in nonhuman primates with renal allografts.J Immunol.1990;144(12): 4604-4612.
17. Nozawa M, Otsu I, Kobayashi H,et al. New immunosuppression with monoclonal antibody to intracellular adhesion molecule 1 (ICAM-1) in rat organ transplantation. Transpl Int. 1992;S521-3.
18. Isobe M, Yagita H, Okumura K, et al. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science. 1992; 28;255(5048):1125-7
19. Buhaescu I, Segall L, Goldsmith D, et al. New immunosuppressive therapies in renal transplantation: monoclonal antibodies. J Nephrol, 2005 ;18(5):529-536.
20. Stepkowski SM, Tu Y, Condon TP,et al. Blocking of heart allograft rejection by intercellular adhesion molecule-1 antisense oligonucleotides alone or in combination with other immunosuppressive modalities. J Immunol. 1994 ;153(11):5336-46
21. Obika S,Hemamayi R,Masuda T, et al. Inhibition of ICAM-1 gene expression by antisense 2',4',-BNA oligonucleotides.Nucleic Acids Res Suppl.2001;(1):145-146.
22. Cheng QL,Chen XM, Li F,et al .Effects of ICAM-1 antisense oligonucleotide on the tubulointerstitium in mice with unilateral uretera obstruction.Kidney Int.2000; 57(1):183-190.
23. Stekowski SM. Development of antisense oligodeoxy nucleotides for transplantation.Curr Opin Mol Ther .2000: 2(3):304一317.
24. Salmela K. Wramner L. Ekberg H,et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation, 1999;67(5):729-36
25. Katz SM, Browne B, Phan T,et al. Efficacy of ICAM-1 antisense oligonucleotide in pancreatic islet transplantation. Transplant Proc,1995;27(6):3214
26. Maldonado M, Baybis M, Newman D,et al.Expression of ICAM-1,TNF-alpha, NF kappa B and MAP kinase in tubers of the tuberous sclerosis complex.Neurobiol Dis.2003:14 (2):279-290.
27. Audette M, Larouche L, Lussier I,et a1. Stimulation of the ICAM-1 gene transcription by the peroxovanadium compound [bpV(Pic)]involves STAT-1 but not NF-kappa B activation in 293 ce1ls.Eur J Biochem.2001:268 (6):1828-1836.
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