重组腺相关病毒-LIGHT对小鼠宫颈癌模型的治疗作用研究
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摘要
第一部分(Part I)
重组腺相关病毒-LIGHT对小鼠宫颈癌模型的
治疗作用研究
[摘要]目的构建含肿瘤坏死因子超家族成员14(LIGHT)的重组腺相关病毒(rAAV-LIGHT),探讨(rAAV-LIGHT)对TC-1细胞株所建立的小鼠宫颈癌模型的抑瘤效应的可行性。方法用基因重组方法构建含LIGHT全长的重组腺相关病毒骨架质粒pAAV-IRES-LIGHT-hrGFP,磷酸钙沉淀法将腺相关病毒载体系统共转染入病毒包装细胞中,分别合成rAAV-LIGHT和rAAV-GFP。并用实时荧光定量PCR测病毒滴度。RT-PCR检测rAAV-LIGHT对TC-1细胞的转染效率。体外用淋巴毒性试验来检测LIGHT的免疫效应。小鼠细胞系TC-1(转染过E6E7RAS)用于建立小鼠宫颈癌模型。成瘤第3天对空白对照组(5只小鼠),rAAV-GFP(5只小鼠), rAAV-LIGHT(5只小鼠)组分别进行肌肉注射。观察其生物特性及用实时定量PCR检测肿瘤微环境中LIGHT和其他细胞因子的表达情况。观察rAAV-LIGHT的抑瘤效应。通过流式细胞仪和肿瘤组织H&E染色、免疫组化检测小鼠淋巴细胞增值效应。结果成功构建并鉴定了rAAV-LIGHT和rAAV-GFP,滴度为2.5×1010 v.g/ml,转染效率为60%。SPSS13.0分析结果显示rAAV-LIGHT组肿瘤大小明显小于对照组及rAAV-GFP组(P=0.0055,P=0.029 P<0.05)。对照组及rAAV-GFP组比较无明显统计学意义(P=0.115 P>0.05)。结论rAAV-LIGHT可在小鼠宫颈癌模型逆转肿瘤生长。
第二部分
(Part 2)携带小鼠HVEM的重组腺相关病毒载体的构建及鉴定
【摘要】目的克隆小鼠疱疹病毒侵入介体(HVEM)基因,构建其重组腺相关病毒载体,鉴定目的基因在真核细胞中表达,为免疫基因治疗奠定基础。方法用RT-PCR法从小鼠脾脏淋巴细胞克隆出全长HVEM基因,构建携带HVEM基因的穿梭质粒pAAV-IRES-HVEM-hrGFP和辅助质粒pAAV-RC,pHelper利用磷酸钙共沉淀法将穿梭质粒共转染入AAV-293细胞中,采用细胞内质粒DNA同源重组法构建重组腺相关病毒rAAV- HVEM。用氯仿-PEG8000法纯化病毒,实时荧光定量PCR测病毒滴度。RT-PCR检测rAAV- HVEM在中国仓鼠卵巢(CHO)细胞中的表达情况。结果成功构建组装重组小鼠HVEM腺相关病毒,纯化后病毒滴度为5×1010 v.g/mL,且在CHO转导细胞中能有效表达目的基因。结论构建的重组腺相关病毒载体rAAV-HVEM为组织工程相关细胞转基因构建及临床应用提供先进的载体系统。为今后进一步研究HVEM的功能及其应用奠定基础。
AAV mediated local delivery of LIGHT suppresses tumor-igenesis in a murine cervical cancer model
[Abstract] Objective To explore the feasibility of reverse effect of recombinant LIGHT adeno-associated virus(rAAV-LIGHT) in mouse cervical cancer model. Methods Using DNA recombination technique to construct AAV main plasmid LIGHT. rAAV-LIGHT and rAAV-GFP were produced by co-transfaction efficiency was measured.The titer was measured by Quantitative Real-time PCR .After transfactin rAAV-LIGHT to TC-1 cells the espression of LIGHT was measured by RT-PCR. Using lymphocyte cytotoxcity assay to test the immunity effects of LIGHT. Mouse cell line TC-1 (transfected by E6E7RAS) was used in the establishment of the cervical cancer model. Three groups of cervical cancer models applied by PBS(as control)(5 mice), rAAV-GFP(5 mice), rAAV-LIGHT(5 mice) intramuscularly on the 3d after innoculation.The biologic feature of the model was observed and the espression of LIGHT and other cytokine experession in the tumor microenvironment was measured by Real-time PCR. Then the effect of rAAV-LIGHT on supperssion tumor growth in models were observed. Analyzed the mice spleen lymphocyte proliferation by flow cytometry, Tumor tissue H&E and Immunohistochemistry. Results rAAV-LIGHT and rAAV-GFP were constructed and identified successfully.The titers were both 2.5×1010 virus particles/ml. The transfection efficiency was 60%. SPSS13.0 analysis showed rAAV-LIGHT group tumor size smaller than control and rAAV-GFP(P=0.0055,P=0.029 P < 0.05). The control and rAAV-GFP group showed no statistically difference in tumor size(P=0.115 P>0.05). Conclusion rAAV-LIGHT could reverse tumor growth in cenrvical cancer model.
Construction and identification of recombinant mouse HVEM adeno-associated virus
【Abstract】Objective To clone mouse HVEM gene into AAV vector pAAV-IRES-hrGFP and obtain high titer and purity recombinant mouse HVEM-AAV and infection of CHO cells for expression, to lay the foundation for immuno-gene therapy. Methods Framework plasmid of recombinant HVEM-AAV was constructed by gene recombination. The recombinant plasmid pAAV-IRES-HVEM-hrGFP , pAAV-RC ,pHelper were co-transfected into AAV-293 cells according to the calcium phosphate based protocol and produced recombinant virus rAAV-HVEM purified by PEG/chloroform. The purity of recombinant rAAV-HVEM was verified by SDS-PAGE. The titer of the virus particles was detected by Quantitative Real-Time PCR. HVEM expression in CHO cells which were infected by recombinant rAAV-HVEM was verified by RT-PCR and FACS analysis. Results Recombinant mouse rAAV-HVEM was successfully constructed with high titer and high purity. After transfection recombinant AAV-HVEM mediated a stable expression of HVEM mRNA in CHO cells。Conclusion Recombinant mouse rAAV-HVEM is successfully constructed, which will benefit for further study the function of HVEM and its applications.
重组腺相关病毒-LIGHT对小鼠宫颈癌模型的
治疗作用研究
[摘要]目的构建含肿瘤坏死因子超家族成员14(LIGHT)的重组腺相关病毒(rAAV-LIGHT),探讨(rAAV-LIGHT)对TC-1细胞株所建立的小鼠宫颈癌模型的抑瘤效应的可行性。方法用基因重组方法构建含LIGHT全长的重组腺相关病毒骨架质粒pAAV-IRES-LIGHT-hrGFP,磷酸钙沉淀法将腺相关病毒载体系统共转染入病毒包装细胞中,分别合成rAAV-LIGHT和rAAV-GFP。并用实时荧光定量PCR测病毒滴度。RT-PCR检测rAAV-LIGHT对TC-1细胞的转染效率。体外用淋巴毒性试验来检测LIGHT的免疫效应。小鼠细胞系TC-1(转染过E6E7RAS)用于建立小鼠宫颈癌模型。成瘤第3天对空白对照组(5只小鼠),rAAV-GFP(5只小鼠), rAAV-LIGHT(5只小鼠)组分别进行肌肉注射。观察其生物特性及用实时定量PCR检测肿瘤微环境中LIGHT和其他细胞因子的表达情况。观察rAAV-LIGHT的抑瘤效应。通过流式细胞仪和肿瘤组织H&E染色、免疫组化检测小鼠淋巴细胞增值效应。结果成功构建并鉴定了rAAV-LIGHT和rAAV-GFP,滴度为2.5×1010 v.g/ml,转染效率为60%。SPSS13.0分析结果显示rAAV-LIGHT组肿瘤大小明显小于对照组及rAAV-GFP组(P=0.0055,P=0.029 P<0.05)。对照组及rAAV-GFP组比较无明显统计学意义(P=0.115 P>0.05)。结论rAAV-LIGHT可在小鼠宫颈癌模型逆转肿瘤生长。
第二部分
(Part 2)携带小鼠HVEM的重组腺相关病毒载体的构建及鉴定
【摘要】目的克隆小鼠疱疹病毒侵入介体(HVEM)基因,构建其重组腺相关病毒载体,鉴定目的基因在真核细胞中表达,为免疫基因治疗奠定基础。方法用RT-PCR法从小鼠脾脏淋巴细胞克隆出全长HVEM基因,构建携带HVEM基因的穿梭质粒pAAV-IRES-HVEM-hrGFP和辅助质粒pAAV-RC,pHelper利用磷酸钙共沉淀法将穿梭质粒共转染入AAV-293细胞中,采用细胞内质粒DNA同源重组法构建重组腺相关病毒rAAV- HVEM。用氯仿-PEG8000法纯化病毒,实时荧光定量PCR测病毒滴度。RT-PCR检测rAAV- HVEM在中国仓鼠卵巢(CHO)细胞中的表达情况。结果成功构建组装重组小鼠HVEM腺相关病毒,纯化后病毒滴度为5×1010 v.g/mL,且在CHO转导细胞中能有效表达目的基因。结论构建的重组腺相关病毒载体rAAV-HVEM为组织工程相关细胞转基因构建及临床应用提供先进的载体系统。为今后进一步研究HVEM的功能及其应用奠定基础。
AAV mediated local delivery of LIGHT suppresses tumor-igenesis in a murine cervical cancer model
[Abstract] Objective To explore the feasibility of reverse effect of recombinant LIGHT adeno-associated virus(rAAV-LIGHT) in mouse cervical cancer model. Methods Using DNA recombination technique to construct AAV main plasmid LIGHT. rAAV-LIGHT and rAAV-GFP were produced by co-transfaction efficiency was measured.The titer was measured by Quantitative Real-time PCR .After transfactin rAAV-LIGHT to TC-1 cells the espression of LIGHT was measured by RT-PCR. Using lymphocyte cytotoxcity assay to test the immunity effects of LIGHT. Mouse cell line TC-1 (transfected by E6E7RAS) was used in the establishment of the cervical cancer model. Three groups of cervical cancer models applied by PBS(as control)(5 mice), rAAV-GFP(5 mice), rAAV-LIGHT(5 mice) intramuscularly on the 3d after innoculation.The biologic feature of the model was observed and the espression of LIGHT and other cytokine experession in the tumor microenvironment was measured by Real-time PCR. Then the effect of rAAV-LIGHT on supperssion tumor growth in models were observed. Analyzed the mice spleen lymphocyte proliferation by flow cytometry, Tumor tissue H&E and Immunohistochemistry. Results rAAV-LIGHT and rAAV-GFP were constructed and identified successfully.The titers were both 2.5×1010 virus particles/ml. The transfection efficiency was 60%. SPSS13.0 analysis showed rAAV-LIGHT group tumor size smaller than control and rAAV-GFP(P=0.0055,P=0.029 P < 0.05). The control and rAAV-GFP group showed no statistically difference in tumor size(P=0.115 P>0.05). Conclusion rAAV-LIGHT could reverse tumor growth in cenrvical cancer model.
Construction and identification of recombinant mouse HVEM adeno-associated virus
【Abstract】Objective To clone mouse HVEM gene into AAV vector pAAV-IRES-hrGFP and obtain high titer and purity recombinant mouse HVEM-AAV and infection of CHO cells for expression, to lay the foundation for immuno-gene therapy. Methods Framework plasmid of recombinant HVEM-AAV was constructed by gene recombination. The recombinant plasmid pAAV-IRES-HVEM-hrGFP , pAAV-RC ,pHelper were co-transfected into AAV-293 cells according to the calcium phosphate based protocol and produced recombinant virus rAAV-HVEM purified by PEG/chloroform. The purity of recombinant rAAV-HVEM was verified by SDS-PAGE. The titer of the virus particles was detected by Quantitative Real-Time PCR. HVEM expression in CHO cells which were infected by recombinant rAAV-HVEM was verified by RT-PCR and FACS analysis. Results Recombinant mouse rAAV-HVEM was successfully constructed with high titer and high purity. After transfection recombinant AAV-HVEM mediated a stable expression of HVEM mRNA in CHO cells。Conclusion Recombinant mouse rAAV-HVEM is successfully constructed, which will benefit for further study the function of HVEM and its applications.
引文
1. Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med,1996;183:725–729。
2. Misawa K, Nosaka T , Kojima T , et al . Molecular cloning and characterization of a mouse homolog of human TNFSF14 , a member of the TNF superfamily. Cytogenet Cell Genet , 2000 , 89 (122) : 89-91.
3. Mauri DN, Ebner R, Montgomery RI, et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity ,1998;8:21–30.
4. Tamada K, Shimozaki K, Chapoval AI, et al. Modulation of T-cell-mediated immunity in tumor and graft-versushost disease models through the LIGHT co-stimulatory pathway. Nat Med, 2000;6:283–289.
5. Rooney IA, Butrovich KD, Glass AA, et al. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem ,2000;275:14307–15.
6. Harrop JA, McDonnell PC, Brigham-Burke M, et al. Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem, 1998;273:27548–56.
7. Kwon BS, Tan KB, Ni J, et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem ,1997;272:14272–6.
8. Murphy M, Walter BN, Pike-Nobile L, et al. Expression of the lymphotoxin beta receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ , 1998;5:497–505.
9. Browning JL, Sizing ID, Lawton P, et al. Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol , 1997; 159: 3288–98.
10. Wang J , Chun T , Lo JC , et al . The critical role of LIGHT , a TNF family member ,in T cell development [J ] . J Immunol , 2001 , 167 (9) : 5099-5105.
11. Harrop JA , McDonnell PC , BrighamBM, et al . Herpesvirus entry mediator ligand (HVEM-L) , a novel ligand for HVEM/ TR2 , stimulates proliferation of T cells and inhibits HT29 cell growth . J Biol Chem , 1998 , 273(42) : 27548-27556
12. Zhai Y, Guo R , Hsu TL , et al . LIGHT , a novel ligand for lymphotoxin beta receptor and TR2/ HVEMinduces apoptosis and suppresses in vivo tumor formation via gene transfer . J Clin Invest , 1998 , 102 (6) : 1142-1151.
13. Wang J , Lo JC , Foster A , et al . The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT . J Clin Invest , 2001 , 108(12) : 1771-1780
14. Ye Q , Fraser CC, Gao W, et al. Modulation of LIGHT-HVEMcostimulation prolongs cardiac allograft survival . J Exp Med , 2002 , 195 (6) :795-800
15. Mauri DN , Ebner R , Montgomery RI , et al . LIGHT , a new member of the TNF superfamily , and lymphotoxin alpha are ligands for herpesvirus entry mediator . Immunity , 1998 , 8 (1) : 21-30.
16. Jackie L. ,Stilwell ,Samulski RJ, et al. Adeno-Associated Virus Vectors for Therapeutic Gene Transfer. Biotechniques , 2003 Jan , 34(1) :148-150 . ?
1. Lee DK, Kim BC, Kim IY, Cho EA, Satterwhite DJ, Kim SJ: The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding of the Smad complex to its target sequence. J Biol Chem 2002, 277(41):38557-38564.
2. Hatch K. Cervical cancer. In: Berek JS, Hacker NF, editors. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins; 1994. p. 243-85.
3. Michelin M, Murta EFC: Potential therapeutic, vaccine strategies and relevance of immune system in uterine cervical cancer. Eur J Gynaecol Oncol, 29: 10-18, 2008.
4. Santin AD, Bellone S, Palmieri M, Zanolini A, Ravaggi A, Siegel ER, Roman JJ, Pecorelli S, CannonMJ: Human papillomavirus 16/18 e7-pulsed dendritic cell vaccination in stage IB-IIA cervical cancer patients; a phase I escalating dose trial. J Virol, 82: 1968-1979, 2008.
5. Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8:21–30
6. Wang JM, Deng X, Gong W, Su S (1998) Chemokines and their role in tumor growth and metastasis.J Immunol Methods 220:1–17.
7. Schneider K, Potter KG, Ware CF (2004) Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev 202:49–66.
8. Morel Y, Truneh A, Sweet RW, Olive D, Costello RT (2001) The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479–2486
9. Richard O Snyder and Terence R Flotte (2002) Production of clinical-grade recombinant adeno-associated virus vectors. Current Opinion in Biotechnology, 13:418–423
10. N C Hasbrouck and K A High(2008)AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospectsProblems and prospects of AAV-mediated gene transfer. Gene Therapy 15, 870-875
11. Song S, Scott-jorgrnsen M, Wang J (2002)Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin(rAAV-SERPINA1)vectors in a nonhuman primate model:safety and immunologic aspects.Mol. Ther.6(3):329-335
12. Enger P?, Thorsen F, L?nning PE, Bjerkvig R, Hoover F (2002) Adeno-Associated Viral Vectors Penetrate Human Solid Tumor Tissue In Vivo More Effectively than Adenoviral Vectors .Human Gene Therapy 13:1115–1125
13. Wu Xiaobing, Dong Xiaoyan, Wu Zhijian(2001) A novel method for purification of recombinant adenoassociated virus vectors on a large scale. Chinese Science Bulletin6(46)485-489
14. Rohr U P, Wulf M A, Stahn S(2002) Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. Journal of Virological Methods 106 (1):81-88
15. Han Xiao, BoHuang,YeYuan,Dong Li, Ling-Fei Han,Yi Liu,Wei Gong, Feng-HuaWu, Gui-Mei Zhang, and Zuo-Hua Feng (2007) Soluble PD-1Facilitates 4-1BBL -Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo.Clin Cancer Res. 13(6):1823-30
16. Daejin Kim, Ratish Gambhir, Balasubramanyam Karanam, Archana Monie, Chien-Fu Hung , Richard Roden,T.-C. Wu (2008) Generation and characterization of a preventive and therapeutic HPV DNA vaccine.Vaccine 26, 351—360
17. Alessandro D. Santin, Stefania Bellone, Michela Palmieri, Alessandro Zanolini(2008) Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial. Journal Of Virology, 82(4):1968–1979
18. Koji Tamada ,Lieping Chen(2006) Renewed interest in cancer immunotherapy with thetumor necrosis factor superfamily molecules. Cancer Immunol Immunother 55: 355–362
19. Tamada K, Shimozaki K, Chapoval AI, Zhai Y, Su J, Chen SF, Hsieh SL, Nagata S, Ni J, Chen L (2000) LIGHT, a TNFlike molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J Immunol 164:4105–4110
20. Tamada K, Shimozaki K, Chapoval AI, Zhu G, Sica G, Flies D, Boone T, Hsu H, Fu YX, Nagata S, Ni J, Chen L (2000) Modulation of T-cell-mediated immunity in tumor and graftversus-host disease models through the LIGHT co-stimulatory pathway. Nat Med 6:283–289.
21. Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8:21–30.
22. Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS (1999) A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 274:13733–13736
23. Browning JL, Sizing ID, Lawton P, Bourdon PR, Rennert PD,Majeau GR, Ambrose CM, Hession C, Miatkowski K, Griffiths DA, Ngam-ek A, Meier W, Benjamin CD, Hochman PS (1997) Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol 159:3288–3298
24. Harrop JA, Reddy M, Dede K, Brigham-Burke M, Lyn S, Tan KB, Silverman C, Eichman C, DiPrinzio R, Spampanato J, Porter T, Holmes S, Young PR, Truneh A (1998) Antibodies to TR2 (herpes virus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J Immunol 161:1786–1794
25. Morel Y, Truneh A, Sweet RW, Olive D, Costello RT (2001) The TNF superfamilymembers LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479–2486
26. Shaikh RB, Santee S, Granger SW, Butrovich K, Cheung T, Kronenberg M, Cheroutre H, Ware CF (2001) Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 167:6330–6337
27. Wang J, Lo JC, Foster A, Yu P, Chen HM, Wang Y, Tamada K, Chen L, Fu YX (2001) The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J Clin Invest 108:1771–1780
28. Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, Schietinger A, Philip M, Schreiber H, Fu YX (2004) Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 5:141–149
29. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, Glader B, Chew AJ, Tai SJ, Herzog RW, Arruda V, Johnson F(2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24:257–61.
30. Chu Q, Moreland R, Yew NS, Foley J, Ziegler R, Scheule RK(2008) Systemic insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. Mol Ther 16:1400–8.
31. Wu Z, Sun J, Zhang T, Yin C, Yin F, Van Dyke T, Samulski RJ, Monahan PE(2008) Optimization of self complementary AAV vectors for liverdirected expression results in sustained correction of hemophilia B at low vector dose. Mol Ther 16:280–9.
32. Park K, Kim WJ, Cho YH, Lee YI, Lee H, Jeong S, Cho ES, Chang SI, Moon SK, Kang BS, Kim YJ, Cho SH(2008) Cancer gene therapy using adeno-associated virus vectors. Front Biosci 13:2653–9.
33. Stedman H, Wilson JM, Finke R, Kleckner AL, Mendell J(2000) Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular instillations of adeno-associatedvectors. Hum Gene Ther 11:777–90.
34. Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP, Spencer LT, Pilewski J, Waltz DA, Dorkin HL, Ferkol T, Pian M(2007) Repeated aerosolized AVCFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther 18:726–32.
1. Rebecca I. Montgomery, Morgyn S. Warner, Brian J. Lum ,et al. Herpes Simplex Virus-1 Entry into Cells Mediated by a Novel Member of the TNF/NGF Receptor Family. Cell, 1996,87:427–436
2. Croft M. The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends in Immunology,2005,26(6):292–294
3. Gavrieli M, Sedy J, Nelson C A, et all. BTLA and HVEM cross talk regulates inhibition and costimulation. Adv Immunol, 2006,92:157-85. Review
4. Cai G, Anumanthan A, Brown JA, et all. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol, 2008 ,9(2):122-124
5. Spear, P. G. 2004. Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol,2004,6(5):401–410
6. Steve W. Granger, Sandra Rickert, et all. LIGHT–HVEM signaling and the regulation of T cell-mediated immunity. Cytokine & Growth Factor Reviews,2003 (3-4):289–296
7. Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature Immunol,2003, 4(7):670–679
8. Cai G, Anumanthan A, Brown J A, et al. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol ,2008,9(2):176–185
9. Ke SONG,Nianjing RAO,Meiling CHEN, et al. Construction of Aneno-associated virus system for Human Bone Morphogenetic Protein 7 Gene. J Huazhong Univ Sci Technol[Med Sci],2008,28,(1):17-21
10. WU Xiaobing, DONG Xiaoyan, WU Zhijian,et all. A novel method for purification of recombinant adenoassociated virus vectors on a large scale. Chinese Science Bulletin ,2001,6(46)485-489
11. Rohr U P, Wulf M A, Stahn S, et all. Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. Journal of Virological Methods ,2002,106 (1):81-88
12. Murphy K M, Nelson C A, Sedy J R. Balancing co-stimulation and inhibition with BTLA and HVEM . Nat Rev Immunol, 2006 ,6(9):671–681
13. Inman B A, Frigola X, Dong H,et all. Costimulation, coinhibition and cancer. Curr Cancer Drug Targets. 2007 ,7(1):15-30
14. Whitbeck J C, Peng C, Lou H,et al. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J Virol ,1997 ,71(8):6083-6093
15. Cheung T C, Humphreys I R, Potter K G, et all. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc Natl Acad Sci U S A,2005 ,102(37):13218-13223
16. Büning H, Perabo L, Coutelle O, et all. Recent developments in adeno-associated virus vector technology. J Gene Med ,2008 ,10(7):717-733
17. Daya S, Berns KI,et all. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev, 2008,21(4):583-593
18. Timothy C. Cheung, Ian R. Humphreys, Karen G. Potter, et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway . PNAS , 2005,102(37):13218–13223
1. Pisani S, Gallinelli C, Seganti L,et al. Detection of viral and bacterial infections in women with normal and abnormal colposcopy. Eur J Gynaecol Oncol .1999;20:69-73.
2. Clifford GM, Smith JS, PlummerM,et al. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88: 63-73.
3. Munoz N, Bosch FX, de SanjoséS, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348: 518-527.
4. Iwasawa A, Nieminen P, Lehtinen M,et al. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996;77(11):2275-9.
5. Walboomers JM, Meijer CJ, Steenbergen RD, et al. Human papillomavirus and the development of cervical cancer: concept of carcinogenesis. Ned Tijdschr Geneeskd. 2000;144(35):1671-4.
6. Ganguly N, Parihar SP. Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis. J Biosci. 2009;34(1):113-23.
7. Bosch FX, Manos MM, Mu?oz N et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995;87(11):796-802.
8. zur Hausen H. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996;1288(2):F55-78.
9. Kirnbauer R, Booy F, Cheng N,et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A. 1992;89(24):12180-4.
10. Crawford SE, LabbéM, Cohen J,et al. Characterization of virus-like particles produced by the expression of rotavirus capsid proteins in insect cells. J Virol. 1994;68(9):5945-52.
11. Zlatkov V. HPV infection and its significance in cervical oncogenesis. Akush Ginekol (Sofiia). 1998;37(1):45-6
12. Wentzensen N, Vinokurova S, von Knebel Doeberitz M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res. 2004;64(11):3878-84
13. McGlennen RC. Human papillomavirus oncogenesis. Clin Lab Med. 2000;20(2):383-406.
14. Ordó?ez RM, Espinosa AM, Sánchez-González DJ,et al. Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription. J Gen Virol. 2004;85(Pt 6):1433-44.
15. Scheffner M, Werness BA, Huibregste JM, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell .1990;63:1129–1136.
16. Kleine-Lowinski K, Rheinwald JG, Fichorova et al. Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells. Int J Cancer. 2003;107(3):407-15.
17. Huang SM, McCance DJ. Down regulation of the interleukin- 8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 andP/CAF. J Virol.2002;76: 8710-8721.
18. de Araujo Souza PS, Sichero L, Maciag PC,et al. HPV variants and HLA polymorphisms: the role of variability on the risk of cervical cancer. Future Oncol. 2009;5(3):359-70.
19. Ashrafi GH, Haghshenas MR, Marchetti B,et al. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. int J Cancer. 2005;113(2):276-83.
20. Kanodia S, Fahey LM, Kast WM. Mechanisms used by human papillomaviruses toescape the host immune response. Curr Cancer Drug Targets .2007;7(1):79–89.
21. Paavonen J, Jenkins D, Bosch FX, et al。Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet . 2007;369:2161-70.
22. Brown DR, Kjaer SK, Sigurdsson K, et al。The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Generally HPV-Naive Women Aged 16-26 Years. J Infect Dis .2009;199:926-35.
23. Ferenczy A, Franco EL. Prophylactic human papillomavirus vaccines: potential for sea change. Expert Rev Vaccines .2007;6:511-25.
24. Christensen ND, Kreider JW, Kan NC, et al. The open reading frame L2 of cottontail rabbit papillomavirus contains antibody-inducing neutralizing epitopes. Virology. 1991;81:572-9.
25. Lin YL, Borenstein LA, Selvakumar R, et al. Effective vaccination against papilloma development by immunization with L1 or L2 structural protein of cottontail rabbit papillomavirus. Virology. 1992;187: 612-9.
26. Chandrachud LM, Grindlay GJ, McGarvie GM, et al. Vaccination of cattle with the N-terminus of L2 is necessary and sufficient for preventing infection by bovine papillomavirus-4. Virology .1995;211:204-8.
27. Gaukroger JM, Chandrachud LM, O'Neil BW, et al. Vaccination of cattle with bovine papillomavirus type 4 L2 elicits the production of virusneutralizing antibodies. J Gen Virol. 1996;77:1577-83.
28. Campo MS, O'Neil BW, Grindlay GJ, et al. A peptide encoding a B-cell epitope from the N-terminus of the capsid protein L2 of bovine papillomavirus-4 prevents disease. Virology. 1997;234:261-6.
29. Roden RB, Yutzy WH 4th, Fallon R, et al. Minor capsid protein of human genitalpapillomaviruses contains subdominant,cross-neutralizing epitopes. Virology. 2000;270:254-7.
30. Jagu S, Karanam B, Gambhira R,et al. Concatenated multitype L2 fusion proteins as candidate prophylactic pan-human papillomavirus vaccines. J Natl Cancer Inst. 2009;101(11):782-92.
31. Hitzeroth II, Passmore JA, Shephard EVaccine, et al. Immunogenicity of an HPV-16 L2 DNA vaccine. 2009;27(46):6432-4.
32. Schellenbacher C, Roden R, Kirnbauer R.Chimeric L1-L2 virus-like particles as potential broad-spectrum human papillomavirus vaccines. J Virol. 2009;83(19):10085-95.
33. Manuri PR, Nehete B, Nehete PN, et al. Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type
16 induces systemic and mucosal cellular immune responses and tumor protection. Vaccine .2007;25(17):3302–3310.
34. Nardelli-Haefliger D, Lurati F, Wirthner D, et al. Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. Vaccine. 2005; 23(28):3634–3641.
35. Sasagawa T, Tani M, Basha W, et al. A human papillomavirus type 16 vaccine by oral delivery of L1 protein. Virus Res. 2005;110(1–2):81–90.
36. Park JS, Oh YK, Kang MJ, et al. Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems. J Med Virol .2003;70(4):633–641.
37. Baez-Astua A, Herraez-Hernandez E, Garbi N, et al. Low-dose adenovirus vaccine encoding chimeric hepatitis B virus surface antigen-human papillomavirus type 16 E7 proteins induces enhanced E7- specific antibody and cytotoxic T-cell responses. J Virol .2005;79(20):12807–12817.
38. Liu DW, Chang JL, Tsao YP, et al. Co-vaccination with adeno-associated virus vectors encoding human papillomavirus 16 L1 proteins and adenovirus encoding murine GMCSF can elicit strong and prolonged neutralizing antibody. Int J Cancer .2005;113(1):93–100.
39. Qian J, Dong Y, Pang YY, et al. Combined prophylactic and therapeutic cancer vaccine: enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. Int J Cancer. 2006;118 (12):3022–3029.
40. Govan VA, Christensen ND, Berkower C, et al. Immunisation with recombinant BCG expressing the cottontail rabbit papillomavirus (CRPV) L1 gene provides protection from CRPV challenge. Vaccine 2006;24(12):2087–2093.
41. Baud D, Ponci F, Bobst M, et al. Improved efficiency of a Salmonella-based vaccine against human papillomavirus type 16 virus-like particles achieved by using a codon-optimized version of L1. J Virol 2004;78(23):12901–12909.
42. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. Jama 2007;298(7):743–753.
43. McNeil C. Search for HPV treatment vaccine heats up, researchers optimistic. J Natl Cancer Inst . 2006;98(14):954–955.
44. Stanley M. Immune responses to human papillomavirus. Vaccine .2006;24:S16–S22.
45. Nakagawa M, Stites D, Patel S, et al. Persistence of Human Papillomavirus 16 infection is associated with lack of cytotoxic T lymphocyte response to the E6 antigen. J Infect Dis. 2000;182:595–598.
46. Peng S, Trimble C, Wu L, et al. HLA-DQB1*02-restricted HPV-16 E7 peptide-specific CD4+ Tcell immune responses correlate with regression of HPV-16-associated high-grade squamous intraepithelial lesions. Clin Cancer Res. 2007;13(8):2479–2487.
47. Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol . 2005;23:975–1028.
48. Hung CF, Tsai YC, He L, et al. DNA Vaccines Encoding Ii-PADRE Generates Potent PADREspecific CD4(+) T-Cell Immune Responses and Enhances Vaccine Potency. Mol Ther. 2007; 15(6):1211–1219.
49. Muderspach L, Wilczynski S, Roman L, et al. A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive. Clin Cancer Res. 2000;6(9):3406–3416.
50. Sheets EE, Urban RG, Crum CP, et al. Immunotherapy of human cervical high-grade cervical intraepithelial neoplasia with microparticle-delivered human papillomavirus
16 E7 plasmid DNA. Am J Obstet Gynecol. 2003;188(4):916–926.
51. Klencke B, Matijevic M, Urban RG, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC101. Clin Cancer Res .2002;8(5):1028–1037.
52. Pockley AG, Muthana M, Calderwood SK. The dual immunoregulatory roles of stress proteins. Trends Biochem Sci. 2008;33(2):71–79.
53. Morris LF, Ribas A. Therapeutic cancer vaccines. Surg Oncol Clin N Am .2007;16(4):819–831.
54. Hallez S, Simon P, Maudoux F, et al. Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia. Cancer Immunol Immunother. 2004;53(7):642–650.
55. Goldstone SE, Palefsky JM, Winnett MT, et al. Activity of HspE7, a novel immunotherapy, in patients with anogenital warts. Dis Colon Rectum. 2002;45(4):502–507.
56. Brandsma JL, Shylankevich M, Su Y, et al. Vesicular stomatitis virus-based therapeutic vaccination targeted to the e1, e2, e6, and e7 proteins of cottontail rabbit papillomavirus. J Virol. 2007;81(11):5749–5758.
57. Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res. 2003 ;63(18):6032–6041.
58. Lin CT, Tsai YC, He L,et al . DNA vaccines encoding IL-2 linked to HPV-16 E7 antigen generate enhanced E7-specific CTL responses and antitumor activity. Immunol Lett. 2007;114(2):86-93.
59. Garcia-Hernandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, et al. Regression of papilloma high-grade lesions (CIN 2 and CIN 3) is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine. Cancer Gene Ther. 2006 Jun;13(6):592–597.
60. Xu YF, Zhang YQ, Xu XM, et al. Papillomavirus virus-like particles as vehicles for the delivery of epitopes or genes. Arch Virol. 2006;151(11):2133–2148.
61. Schreckenberger C, Kaufmann AM. Vaccination strategies for the treatment and prevention of cervical cancer. Curr Opin Oncol. 2004;16(5):485–491.
62. de Jong A, O'Neill T, Khan AY, et al. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine. Vaccine .2002;20(29–30):3456–3464.
63. Steinman RM, Pope M. Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest.2002;109: 1519-1526.
64. Fernandez NC, Lozier A, Flament C,et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med.1999;5: 405-411.
65. Nefedova Y, Nagaraj S, Rosenbauer A,et al. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic- selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res.2005; 65: 9525-9535.
66. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves differentiation ofmyeloid cells and immune
67. response in cancer patients. Cancer Res.2006;66: 9299-9307.
68. Wang S, Hong S,Yang J, et al. Optimizing immunotherapy in multiple myeloma: Restoring the function of patients’monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. Blood.2006;108: 4071-4077.
69. Thurnher M, Radmayr C, Ramoner R,et al. Human renal-cell carcinoma tissue contains dendritic cells. Int J Cancer. 1996;68: 1-7.
70. Lissoni P,Vigore L, Ferranti R, et al. Circulating dendritic cells in early and advanced cancer patients: diminished percent in the metastatic disease. J Biol Regul Homeost Agents.1999; 13: 216-219.
71. Lissoni P, Malugani F, Bonfanti A, et al. Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-12 and endothelin- 1. J Bio Regul Homeos Agents.200115: 140-144.
72. Nguyen XD, Eichler H, Sucker A, et al.Collection of autologous monocytes for dendritic cell vaccination therapy inmetastaticmelanoma patients. Transfusion.2002;42: 428-432.
73. Ambe K, Mori M, Enjoji M.S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis. Cancer.1989;63: 496-503.
74. Lespagnard L, Gancberg D, Rouas G, et al. Tumor- infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome. Int J Cancer. 1999;309-314.
75. YamakawaM, Yamada K, Orui H, et al. Immunohistochemical analysis of dendritic/ Langerhans cells in thyroid carcinomas. Anal Cell Pathol.1995; 8: 331-343.
76. Xie LH, Sin FW, Cheng SC, et al. Activation of cytotoxic T lymphocytes against CML28- bearing tumors by dendritic cells transduced with a recombinant adeno-associated virus encoding the CML28 gene. Cancer Immunol Immunother.2008; 57: 1029-1038.
77. Nabekura T, Nagasawa T, Nakauchi H, et al. An immunotherapy approach with dendritic cells genetically modified to express the tumor-associated antigen, HER2. Cancer Immunol Immunother.2008;57: 611-622.
78. Bercovici N, Haicheur N, Massicard S, et al. Analysis and characterization of antitumor t-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastaticmelanoma patients.J Immunother. 2008;31: 101-112.
79. Santin AD, Bellone S, Palmieri M, et al. Human papillomavirus 16/18 e7-pulsed dendritic cell vaccination in stage IB-IIA cervical cancer patients; a phase I escalating dose trial. J Virol.2008; 82: 1968-1979.
2. Misawa K, Nosaka T , Kojima T , et al . Molecular cloning and characterization of a mouse homolog of human TNFSF14 , a member of the TNF superfamily. Cytogenet Cell Genet , 2000 , 89 (122) : 89-91.
3. Mauri DN, Ebner R, Montgomery RI, et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity ,1998;8:21–30.
4. Tamada K, Shimozaki K, Chapoval AI, et al. Modulation of T-cell-mediated immunity in tumor and graft-versushost disease models through the LIGHT co-stimulatory pathway. Nat Med, 2000;6:283–289.
5. Rooney IA, Butrovich KD, Glass AA, et al. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem ,2000;275:14307–15.
6. Harrop JA, McDonnell PC, Brigham-Burke M, et al. Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J Biol Chem, 1998;273:27548–56.
7. Kwon BS, Tan KB, Ni J, et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem ,1997;272:14272–6.
8. Murphy M, Walter BN, Pike-Nobile L, et al. Expression of the lymphotoxin beta receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ , 1998;5:497–505.
9. Browning JL, Sizing ID, Lawton P, et al. Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol , 1997; 159: 3288–98.
10. Wang J , Chun T , Lo JC , et al . The critical role of LIGHT , a TNF family member ,in T cell development [J ] . J Immunol , 2001 , 167 (9) : 5099-5105.
11. Harrop JA , McDonnell PC , BrighamBM, et al . Herpesvirus entry mediator ligand (HVEM-L) , a novel ligand for HVEM/ TR2 , stimulates proliferation of T cells and inhibits HT29 cell growth . J Biol Chem , 1998 , 273(42) : 27548-27556
12. Zhai Y, Guo R , Hsu TL , et al . LIGHT , a novel ligand for lymphotoxin beta receptor and TR2/ HVEMinduces apoptosis and suppresses in vivo tumor formation via gene transfer . J Clin Invest , 1998 , 102 (6) : 1142-1151.
13. Wang J , Lo JC , Foster A , et al . The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT . J Clin Invest , 2001 , 108(12) : 1771-1780
14. Ye Q , Fraser CC, Gao W, et al. Modulation of LIGHT-HVEMcostimulation prolongs cardiac allograft survival . J Exp Med , 2002 , 195 (6) :795-800
15. Mauri DN , Ebner R , Montgomery RI , et al . LIGHT , a new member of the TNF superfamily , and lymphotoxin alpha are ligands for herpesvirus entry mediator . Immunity , 1998 , 8 (1) : 21-30.
16. Jackie L. ,Stilwell ,Samulski RJ, et al. Adeno-Associated Virus Vectors for Therapeutic Gene Transfer. Biotechniques , 2003 Jan , 34(1) :148-150 . ?
1. Lee DK, Kim BC, Kim IY, Cho EA, Satterwhite DJ, Kim SJ: The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding of the Smad complex to its target sequence. J Biol Chem 2002, 277(41):38557-38564.
2. Hatch K. Cervical cancer. In: Berek JS, Hacker NF, editors. Practical gynecologic oncology. 2nd ed. Baltimore: Williams & Wilkins; 1994. p. 243-85.
3. Michelin M, Murta EFC: Potential therapeutic, vaccine strategies and relevance of immune system in uterine cervical cancer. Eur J Gynaecol Oncol, 29: 10-18, 2008.
4. Santin AD, Bellone S, Palmieri M, Zanolini A, Ravaggi A, Siegel ER, Roman JJ, Pecorelli S, CannonMJ: Human papillomavirus 16/18 e7-pulsed dendritic cell vaccination in stage IB-IIA cervical cancer patients; a phase I escalating dose trial. J Virol, 82: 1968-1979, 2008.
5. Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8:21–30
6. Wang JM, Deng X, Gong W, Su S (1998) Chemokines and their role in tumor growth and metastasis.J Immunol Methods 220:1–17.
7. Schneider K, Potter KG, Ware CF (2004) Lymphotoxin and LIGHT signaling pathways and target genes. Immunol Rev 202:49–66.
8. Morel Y, Truneh A, Sweet RW, Olive D, Costello RT (2001) The TNF superfamily members LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479–2486
9. Richard O Snyder and Terence R Flotte (2002) Production of clinical-grade recombinant adeno-associated virus vectors. Current Opinion in Biotechnology, 13:418–423
10. N C Hasbrouck and K A High(2008)AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospectsProblems and prospects of AAV-mediated gene transfer. Gene Therapy 15, 870-875
11. Song S, Scott-jorgrnsen M, Wang J (2002)Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin(rAAV-SERPINA1)vectors in a nonhuman primate model:safety and immunologic aspects.Mol. Ther.6(3):329-335
12. Enger P?, Thorsen F, L?nning PE, Bjerkvig R, Hoover F (2002) Adeno-Associated Viral Vectors Penetrate Human Solid Tumor Tissue In Vivo More Effectively than Adenoviral Vectors .Human Gene Therapy 13:1115–1125
13. Wu Xiaobing, Dong Xiaoyan, Wu Zhijian(2001) A novel method for purification of recombinant adenoassociated virus vectors on a large scale. Chinese Science Bulletin6(46)485-489
14. Rohr U P, Wulf M A, Stahn S(2002) Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. Journal of Virological Methods 106 (1):81-88
15. Han Xiao, BoHuang,YeYuan,Dong Li, Ling-Fei Han,Yi Liu,Wei Gong, Feng-HuaWu, Gui-Mei Zhang, and Zuo-Hua Feng (2007) Soluble PD-1Facilitates 4-1BBL -Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo.Clin Cancer Res. 13(6):1823-30
16. Daejin Kim, Ratish Gambhir, Balasubramanyam Karanam, Archana Monie, Chien-Fu Hung , Richard Roden,T.-C. Wu (2008) Generation and characterization of a preventive and therapeutic HPV DNA vaccine.Vaccine 26, 351—360
17. Alessandro D. Santin, Stefania Bellone, Michela Palmieri, Alessandro Zanolini(2008) Human Papillomavirus Type 16 and 18 E7-Pulsed Dendritic Cell Vaccination of Stage IB or IIA Cervical Cancer Patients: a Phase I Escalating-Dose Trial. Journal Of Virology, 82(4):1968–1979
18. Koji Tamada ,Lieping Chen(2006) Renewed interest in cancer immunotherapy with thetumor necrosis factor superfamily molecules. Cancer Immunol Immunother 55: 355–362
19. Tamada K, Shimozaki K, Chapoval AI, Zhai Y, Su J, Chen SF, Hsieh SL, Nagata S, Ni J, Chen L (2000) LIGHT, a TNFlike molecule, costimulates T cell proliferation and is required for dendritic cell-mediated allogeneic T cell response. J Immunol 164:4105–4110
20. Tamada K, Shimozaki K, Chapoval AI, Zhu G, Sica G, Flies D, Boone T, Hsu H, Fu YX, Nagata S, Ni J, Chen L (2000) Modulation of T-cell-mediated immunity in tumor and graftversus-host disease models through the LIGHT co-stimulatory pathway. Nat Med 6:283–289.
21. Mauri DN, Ebner R, Montgomery RI, Kochel KD, Cheung TC, Yu GL, Ruben S, Murphy M, Eisenberg RJ, Cohen GH, Spear PG, Ware CF (1998) LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 8:21–30.
22. Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS (1999) A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem 274:13733–13736
23. Browning JL, Sizing ID, Lawton P, Bourdon PR, Rennert PD,Majeau GR, Ambrose CM, Hession C, Miatkowski K, Griffiths DA, Ngam-ek A, Meier W, Benjamin CD, Hochman PS (1997) Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes. J Immunol 159:3288–3298
24. Harrop JA, Reddy M, Dede K, Brigham-Burke M, Lyn S, Tan KB, Silverman C, Eichman C, DiPrinzio R, Spampanato J, Porter T, Holmes S, Young PR, Truneh A (1998) Antibodies to TR2 (herpes virus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J Immunol 161:1786–1794
25. Morel Y, Truneh A, Sweet RW, Olive D, Costello RT (2001) The TNF superfamilymembers LIGHT and CD154 (CD40 ligand) costimulate induction of dendritic cell maturation and elicit specific CTL activity. J Immunol 167:2479–2486
26. Shaikh RB, Santee S, Granger SW, Butrovich K, Cheung T, Kronenberg M, Cheroutre H, Ware CF (2001) Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction. J Immunol 167:6330–6337
27. Wang J, Lo JC, Foster A, Yu P, Chen HM, Wang Y, Tamada K, Chen L, Fu YX (2001) The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J Clin Invest 108:1771–1780
28. Yu P, Lee Y, Liu W, Chin RK, Wang J, Wang Y, Schietinger A, Philip M, Schreiber H, Fu YX (2004) Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 5:141–149
29. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, Glader B, Chew AJ, Tai SJ, Herzog RW, Arruda V, Johnson F(2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24:257–61.
30. Chu Q, Moreland R, Yew NS, Foley J, Ziegler R, Scheule RK(2008) Systemic insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. Mol Ther 16:1400–8.
31. Wu Z, Sun J, Zhang T, Yin C, Yin F, Van Dyke T, Samulski RJ, Monahan PE(2008) Optimization of self complementary AAV vectors for liverdirected expression results in sustained correction of hemophilia B at low vector dose. Mol Ther 16:280–9.
32. Park K, Kim WJ, Cho YH, Lee YI, Lee H, Jeong S, Cho ES, Chang SI, Moon SK, Kang BS, Kim YJ, Cho SH(2008) Cancer gene therapy using adeno-associated virus vectors. Front Biosci 13:2653–9.
33. Stedman H, Wilson JM, Finke R, Kleckner AL, Mendell J(2000) Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: alpha-, beta-, gamma-, or delta-sarcoglycan gene delivered with intramuscular instillations of adeno-associatedvectors. Hum Gene Ther 11:777–90.
34. Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP, Spencer LT, Pilewski J, Waltz DA, Dorkin HL, Ferkol T, Pian M(2007) Repeated aerosolized AVCFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther 18:726–32.
1. Rebecca I. Montgomery, Morgyn S. Warner, Brian J. Lum ,et al. Herpes Simplex Virus-1 Entry into Cells Mediated by a Novel Member of the TNF/NGF Receptor Family. Cell, 1996,87:427–436
2. Croft M. The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends in Immunology,2005,26(6):292–294
3. Gavrieli M, Sedy J, Nelson C A, et all. BTLA and HVEM cross talk regulates inhibition and costimulation. Adv Immunol, 2006,92:157-85. Review
4. Cai G, Anumanthan A, Brown JA, et all. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol, 2008 ,9(2):122-124
5. Spear, P. G. 2004. Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol,2004,6(5):401–410
6. Steve W. Granger, Sandra Rickert, et all. LIGHT–HVEM signaling and the regulation of T cell-mediated immunity. Cytokine & Growth Factor Reviews,2003 (3-4):289–296
7. Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nature Immunol,2003, 4(7):670–679
8. Cai G, Anumanthan A, Brown J A, et al. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol ,2008,9(2):176–185
9. Ke SONG,Nianjing RAO,Meiling CHEN, et al. Construction of Aneno-associated virus system for Human Bone Morphogenetic Protein 7 Gene. J Huazhong Univ Sci Technol[Med Sci],2008,28,(1):17-21
10. WU Xiaobing, DONG Xiaoyan, WU Zhijian,et all. A novel method for purification of recombinant adenoassociated virus vectors on a large scale. Chinese Science Bulletin ,2001,6(46)485-489
11. Rohr U P, Wulf M A, Stahn S, et all. Fast and reliable titration of recombinant adeno-associated virus type-2 using quantitative real-time PCR. Journal of Virological Methods ,2002,106 (1):81-88
12. Murphy K M, Nelson C A, Sedy J R. Balancing co-stimulation and inhibition with BTLA and HVEM . Nat Rev Immunol, 2006 ,6(9):671–681
13. Inman B A, Frigola X, Dong H,et all. Costimulation, coinhibition and cancer. Curr Cancer Drug Targets. 2007 ,7(1):15-30
14. Whitbeck J C, Peng C, Lou H,et al. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the tumor necrosis factor receptor superfamily and a mediator of HSV entry. J Virol ,1997 ,71(8):6083-6093
15. Cheung T C, Humphreys I R, Potter K G, et all. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. Proc Natl Acad Sci U S A,2005 ,102(37):13218-13223
16. Büning H, Perabo L, Coutelle O, et all. Recent developments in adeno-associated virus vector technology. J Gene Med ,2008 ,10(7):717-733
17. Daya S, Berns KI,et all. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev, 2008,21(4):583-593
18. Timothy C. Cheung, Ian R. Humphreys, Karen G. Potter, et al. Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway . PNAS , 2005,102(37):13218–13223
1. Pisani S, Gallinelli C, Seganti L,et al. Detection of viral and bacterial infections in women with normal and abnormal colposcopy. Eur J Gynaecol Oncol .1999;20:69-73.
2. Clifford GM, Smith JS, PlummerM,et al. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88: 63-73.
3. Munoz N, Bosch FX, de SanjoséS, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348: 518-527.
4. Iwasawa A, Nieminen P, Lehtinen M,et al. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996;77(11):2275-9.
5. Walboomers JM, Meijer CJ, Steenbergen RD, et al. Human papillomavirus and the development of cervical cancer: concept of carcinogenesis. Ned Tijdschr Geneeskd. 2000;144(35):1671-4.
6. Ganguly N, Parihar SP. Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis. J Biosci. 2009;34(1):113-23.
7. Bosch FX, Manos MM, Mu?oz N et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995;87(11):796-802.
8. zur Hausen H. Papillomavirus infections--a major cause of human cancers. Biochim Biophys Acta. 1996;1288(2):F55-78.
9. Kirnbauer R, Booy F, Cheng N,et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A. 1992;89(24):12180-4.
10. Crawford SE, LabbéM, Cohen J,et al. Characterization of virus-like particles produced by the expression of rotavirus capsid proteins in insect cells. J Virol. 1994;68(9):5945-52.
11. Zlatkov V. HPV infection and its significance in cervical oncogenesis. Akush Ginekol (Sofiia). 1998;37(1):45-6
12. Wentzensen N, Vinokurova S, von Knebel Doeberitz M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res. 2004;64(11):3878-84
13. McGlennen RC. Human papillomavirus oncogenesis. Clin Lab Med. 2000;20(2):383-406.
14. Ordó?ez RM, Espinosa AM, Sánchez-González DJ,et al. Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription. J Gen Virol. 2004;85(Pt 6):1433-44.
15. Scheffner M, Werness BA, Huibregste JM, et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell .1990;63:1129–1136.
16. Kleine-Lowinski K, Rheinwald JG, Fichorova et al. Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells. Int J Cancer. 2003;107(3):407-15.
17. Huang SM, McCance DJ. Down regulation of the interleukin- 8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 andP/CAF. J Virol.2002;76: 8710-8721.
18. de Araujo Souza PS, Sichero L, Maciag PC,et al. HPV variants and HLA polymorphisms: the role of variability on the risk of cervical cancer. Future Oncol. 2009;5(3):359-70.
19. Ashrafi GH, Haghshenas MR, Marchetti B,et al. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. int J Cancer. 2005;113(2):276-83.
20. Kanodia S, Fahey LM, Kast WM. Mechanisms used by human papillomaviruses toescape the host immune response. Curr Cancer Drug Targets .2007;7(1):79–89.
21. Paavonen J, Jenkins D, Bosch FX, et al。Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet . 2007;369:2161-70.
22. Brown DR, Kjaer SK, Sigurdsson K, et al。The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Generally HPV-Naive Women Aged 16-26 Years. J Infect Dis .2009;199:926-35.
23. Ferenczy A, Franco EL. Prophylactic human papillomavirus vaccines: potential for sea change. Expert Rev Vaccines .2007;6:511-25.
24. Christensen ND, Kreider JW, Kan NC, et al. The open reading frame L2 of cottontail rabbit papillomavirus contains antibody-inducing neutralizing epitopes. Virology. 1991;81:572-9.
25. Lin YL, Borenstein LA, Selvakumar R, et al. Effective vaccination against papilloma development by immunization with L1 or L2 structural protein of cottontail rabbit papillomavirus. Virology. 1992;187: 612-9.
26. Chandrachud LM, Grindlay GJ, McGarvie GM, et al. Vaccination of cattle with the N-terminus of L2 is necessary and sufficient for preventing infection by bovine papillomavirus-4. Virology .1995;211:204-8.
27. Gaukroger JM, Chandrachud LM, O'Neil BW, et al. Vaccination of cattle with bovine papillomavirus type 4 L2 elicits the production of virusneutralizing antibodies. J Gen Virol. 1996;77:1577-83.
28. Campo MS, O'Neil BW, Grindlay GJ, et al. A peptide encoding a B-cell epitope from the N-terminus of the capsid protein L2 of bovine papillomavirus-4 prevents disease. Virology. 1997;234:261-6.
29. Roden RB, Yutzy WH 4th, Fallon R, et al. Minor capsid protein of human genitalpapillomaviruses contains subdominant,cross-neutralizing epitopes. Virology. 2000;270:254-7.
30. Jagu S, Karanam B, Gambhira R,et al. Concatenated multitype L2 fusion proteins as candidate prophylactic pan-human papillomavirus vaccines. J Natl Cancer Inst. 2009;101(11):782-92.
31. Hitzeroth II, Passmore JA, Shephard EVaccine, et al. Immunogenicity of an HPV-16 L2 DNA vaccine. 2009;27(46):6432-4.
32. Schellenbacher C, Roden R, Kirnbauer R.Chimeric L1-L2 virus-like particles as potential broad-spectrum human papillomavirus vaccines. J Virol. 2009;83(19):10085-95.
33. Manuri PR, Nehete B, Nehete PN, et al. Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type
16 induces systemic and mucosal cellular immune responses and tumor protection. Vaccine .2007;25(17):3302–3310.
34. Nardelli-Haefliger D, Lurati F, Wirthner D, et al. Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. Vaccine. 2005; 23(28):3634–3641.
35. Sasagawa T, Tani M, Basha W, et al. A human papillomavirus type 16 vaccine by oral delivery of L1 protein. Virus Res. 2005;110(1–2):81–90.
36. Park JS, Oh YK, Kang MJ, et al. Enhanced mucosal and systemic immune responses following intravaginal immunization with human papillomavirus 16 L1 virus-like particle vaccine in thermosensitive mucoadhesive delivery systems. J Med Virol .2003;70(4):633–641.
37. Baez-Astua A, Herraez-Hernandez E, Garbi N, et al. Low-dose adenovirus vaccine encoding chimeric hepatitis B virus surface antigen-human papillomavirus type 16 E7 proteins induces enhanced E7- specific antibody and cytotoxic T-cell responses. J Virol .2005;79(20):12807–12817.
38. Liu DW, Chang JL, Tsao YP, et al. Co-vaccination with adeno-associated virus vectors encoding human papillomavirus 16 L1 proteins and adenovirus encoding murine GMCSF can elicit strong and prolonged neutralizing antibody. Int J Cancer .2005;113(1):93–100.
39. Qian J, Dong Y, Pang YY, et al. Combined prophylactic and therapeutic cancer vaccine: enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. Int J Cancer. 2006;118 (12):3022–3029.
40. Govan VA, Christensen ND, Berkower C, et al. Immunisation with recombinant BCG expressing the cottontail rabbit papillomavirus (CRPV) L1 gene provides protection from CRPV challenge. Vaccine 2006;24(12):2087–2093.
41. Baud D, Ponci F, Bobst M, et al. Improved efficiency of a Salmonella-based vaccine against human papillomavirus type 16 virus-like particles achieved by using a codon-optimized version of L1. J Virol 2004;78(23):12901–12909.
42. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. Jama 2007;298(7):743–753.
43. McNeil C. Search for HPV treatment vaccine heats up, researchers optimistic. J Natl Cancer Inst . 2006;98(14):954–955.
44. Stanley M. Immune responses to human papillomavirus. Vaccine .2006;24:S16–S22.
45. Nakagawa M, Stites D, Patel S, et al. Persistence of Human Papillomavirus 16 infection is associated with lack of cytotoxic T lymphocyte response to the E6 antigen. J Infect Dis. 2000;182:595–598.
46. Peng S, Trimble C, Wu L, et al. HLA-DQB1*02-restricted HPV-16 E7 peptide-specific CD4+ Tcell immune responses correlate with regression of HPV-16-associated high-grade squamous intraepithelial lesions. Clin Cancer Res. 2007;13(8):2479–2487.
47. Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol . 2005;23:975–1028.
48. Hung CF, Tsai YC, He L, et al. DNA Vaccines Encoding Ii-PADRE Generates Potent PADREspecific CD4(+) T-Cell Immune Responses and Enhances Vaccine Potency. Mol Ther. 2007; 15(6):1211–1219.
49. Muderspach L, Wilczynski S, Roman L, et al. A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive. Clin Cancer Res. 2000;6(9):3406–3416.
50. Sheets EE, Urban RG, Crum CP, et al. Immunotherapy of human cervical high-grade cervical intraepithelial neoplasia with microparticle-delivered human papillomavirus
16 E7 plasmid DNA. Am J Obstet Gynecol. 2003;188(4):916–926.
51. Klencke B, Matijevic M, Urban RG, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC101. Clin Cancer Res .2002;8(5):1028–1037.
52. Pockley AG, Muthana M, Calderwood SK. The dual immunoregulatory roles of stress proteins. Trends Biochem Sci. 2008;33(2):71–79.
53. Morris LF, Ribas A. Therapeutic cancer vaccines. Surg Oncol Clin N Am .2007;16(4):819–831.
54. Hallez S, Simon P, Maudoux F, et al. Phase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia. Cancer Immunol Immunother. 2004;53(7):642–650.
55. Goldstone SE, Palefsky JM, Winnett MT, et al. Activity of HspE7, a novel immunotherapy, in patients with anogenital warts. Dis Colon Rectum. 2002;45(4):502–507.
56. Brandsma JL, Shylankevich M, Su Y, et al. Vesicular stomatitis virus-based therapeutic vaccination targeted to the e1, e2, e6, and e7 proteins of cottontail rabbit papillomavirus. J Virol. 2007;81(11):5749–5758.
57. Davidson EJ, Boswell CM, Sehr P, et al. Immunological and clinical responses in women with vulval intraepithelial neoplasia vaccinated with a vaccinia virus encoding human papillomavirus 16/18 oncoproteins. Cancer Res. 2003 ;63(18):6032–6041.
58. Lin CT, Tsai YC, He L,et al . DNA vaccines encoding IL-2 linked to HPV-16 E7 antigen generate enhanced E7-specific CTL responses and antitumor activity. Immunol Lett. 2007;114(2):86-93.
59. Garcia-Hernandez E, Gonzalez-Sanchez JL, Andrade-Manzano A, et al. Regression of papilloma high-grade lesions (CIN 2 and CIN 3) is stimulated by therapeutic vaccination with MVA E2 recombinant vaccine. Cancer Gene Ther. 2006 Jun;13(6):592–597.
60. Xu YF, Zhang YQ, Xu XM, et al. Papillomavirus virus-like particles as vehicles for the delivery of epitopes or genes. Arch Virol. 2006;151(11):2133–2148.
61. Schreckenberger C, Kaufmann AM. Vaccination strategies for the treatment and prevention of cervical cancer. Curr Opin Oncol. 2004;16(5):485–491.
62. de Jong A, O'Neill T, Khan AY, et al. Enhancement of human papillomavirus (HPV) type 16 E6 and E7-specific T-cell immunity in healthy volunteers through vaccination with TA-CIN, an HPV16 L2E7E6 fusion protein vaccine. Vaccine .2002;20(29–30):3456–3464.
63. Steinman RM, Pope M. Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest.2002;109: 1519-1526.
64. Fernandez NC, Lozier A, Flament C,et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med.1999;5: 405-411.
65. Nefedova Y, Nagaraj S, Rosenbauer A,et al. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic- selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res.2005; 65: 9525-9535.
66. Mirza N, Fishman M, Fricke I, et al. All-trans-retinoic acid improves differentiation ofmyeloid cells and immune
67. response in cancer patients. Cancer Res.2006;66: 9299-9307.
68. Wang S, Hong S,Yang J, et al. Optimizing immunotherapy in multiple myeloma: Restoring the function of patients’monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. Blood.2006;108: 4071-4077.
69. Thurnher M, Radmayr C, Ramoner R,et al. Human renal-cell carcinoma tissue contains dendritic cells. Int J Cancer. 1996;68: 1-7.
70. Lissoni P,Vigore L, Ferranti R, et al. Circulating dendritic cells in early and advanced cancer patients: diminished percent in the metastatic disease. J Biol Regul Homeost Agents.1999; 13: 216-219.
71. Lissoni P, Malugani F, Bonfanti A, et al. Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-12 and endothelin- 1. J Bio Regul Homeos Agents.200115: 140-144.
72. Nguyen XD, Eichler H, Sucker A, et al.Collection of autologous monocytes for dendritic cell vaccination therapy inmetastaticmelanoma patients. Transfusion.2002;42: 428-432.
73. Ambe K, Mori M, Enjoji M.S-100 protein-positive dendritic cells in colorectal adenocarcinomas. Distribution and relation to the clinical prognosis. Cancer.1989;63: 496-503.
74. Lespagnard L, Gancberg D, Rouas G, et al. Tumor- infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome. Int J Cancer. 1999;309-314.
75. YamakawaM, Yamada K, Orui H, et al. Immunohistochemical analysis of dendritic/ Langerhans cells in thyroid carcinomas. Anal Cell Pathol.1995; 8: 331-343.
76. Xie LH, Sin FW, Cheng SC, et al. Activation of cytotoxic T lymphocytes against CML28- bearing tumors by dendritic cells transduced with a recombinant adeno-associated virus encoding the CML28 gene. Cancer Immunol Immunother.2008; 57: 1029-1038.
77. Nabekura T, Nagasawa T, Nakauchi H, et al. An immunotherapy approach with dendritic cells genetically modified to express the tumor-associated antigen, HER2. Cancer Immunol Immunother.2008;57: 611-622.
78. Bercovici N, Haicheur N, Massicard S, et al. Analysis and characterization of antitumor t-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastaticmelanoma patients.J Immunother. 2008;31: 101-112.
79. Santin AD, Bellone S, Palmieri M, et al. Human papillomavirus 16/18 e7-pulsed dendritic cell vaccination in stage IB-IIA cervical cancer patients; a phase I escalating dose trial. J Virol.2008; 82: 1968-1979.