(3.231.230.175) 您好!臺灣時間:2021/04/16 01:39
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:孔德歆
研究生(外文):Kung, Te-Hsin
論文名稱:腸病毒非結構蛋白之免疫性與針對EV71與CVA16之交叉保護效果
論文名稱(外文):The Immunogenicity of Non-Structure Protein Derived from Enterovirus Cross-Protects EV71 and CVA16 Infections
指導教授:周彥宏張晃猷
指導教授(外文):Chow, Yen-HongChang, Hwan-You
口試委員:劉家齊吳尚蓉
口試委員(外文):Liu, Chia-ChyiWu, Shang-Rung
口試日期:2019-2-27
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:64
中文關鍵詞:腸病毒非結構蛋白疫苗佐劑
外文關鍵詞:enterovirusnon-structure proteinvaccineadjuvant
相關次數:
  • 被引用被引用:0
  • 點閱點閱:67
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:1
  • 收藏至我的研究室書目清單書目收藏:0
腸病毒71型(Enterovirus 71,EV71)與克沙奇病毒A16(Coxsackievirus A16)為手足口病主要病原,好發於學齡前幼童, EV71與CVA16皆屬於微小核糖核酸病毒(Picornavirus),兩者的3Dpol聚合酶(3Dpol polymerase)具有至少90%的相似度。本實驗室先前以腺病毒作為載體,插入EV71 3CD基因序列,打入h-SCARB2轉基因老鼠成功抵抗EV71以及CVA16,顯示3Dpol可能具有的保護力。在本研究中,建立重組3Dpol之質體建構並且以大腸桿菌進行生產。首先,接種單純3Dpol的h-SCARB2小鼠無法存活於CVA16攻毒。接著,將3Dpol混合R848、IFA或ISA-51對小鼠接種,發現3Dpol/R848可以保護小鼠於EV71攻毒,而3Dpol/IFA可以保護小鼠於CVA16攻毒,並且3Dpol/ISA-51可以交叉保護小鼠於EV71或CVA16攻毒。其中,接種3Dpol/R848或3Dpol/ISA-51之小鼠其脾臟能表現較高水準之IL-4與IL-17a,然而不管是接種3Dpol/R848、3Dpol/ISA-51或是3Dpol/IFA,都表現較少IFN-gamma。同時,接種3Dpol/ISA-51之小鼠,其體內的CD4+ T cell有被負向調節的現象。最後,從3Dpol/R848、3Dpol/ISA-51或3Dpol/IFA接種之小鼠取得之血清,無法降低EV71造成之細胞病變現象。這些數據顯示3Dpol搭配佐劑不只能保護小鼠免於感染,並可能對IFN-gamma+CD4+ and IL-4+CD4+ T cell有克隆選擇之作用。
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative for hand, foot and mouth disease, a common disease found on children. EV71 and CVA16 are the member of the picornaviridae family. Their 3Dpol polymerase share 90% of homology at least. Previously, an adenovirus, inserted with 3CD sequence, was developed in our lab and found that being able to protect h-SCARB2 mice from EV71 and CVA16. This finding suggests that the protective ability might be distributed by 3Dpol. First, in this research, the construct of recombinant 3Dpol was developed and produced. Then, the h-SCARB2 mice were immunized with 3Dpol alone and no mice survived under CVA16 subsequent challenge. Afterwards, the 3Dpol was mixed with R848, IFA and ISA-51. Results showed that 3Dpol with R848 or IFA can protect h-SCARB2 mice from EV71 or CVA16 respectively. Most importantly, 3Dpol mixed with ISA-51 can cross protect h-SCARB2 mice from both EV71 and CVA16. Besides, the Th2 and Th17 cytokine were expressed higher by the splenocytes immunized with 3Dpol/ISA-51 and 3Dpol/R848. However, the expression level of IFN-γ was decreased and the CD4+ T cell proliferation was down-regulated. Final, the serum derived from 3Dpol/R848, IFA or ISA-51 could not reduce the cytopathic effect caused by EV71. These results suggest that the 3Dpol with adjuvant not only can protect mice from infection but also may contribute to the clonal selection of IFN-gamma+CD4+ and IL-4+CD4+ T cell.
Abstract…………………………………………………………………….………………i
中文摘要…………………………………………………………………………………ii
謝誌………………………………………………………………………………………iii
縮寫檢索表………………………………………………………………………………iv
目錄………………………………………………………………………………………v
表目錄……………………………………………………………………………………vii
圖目錄…………………………………………………………………………………viii
I 緒論………………………………………………………………………………1
I-1 腸病毒疫情與手足口病症狀回顧………………………….…………………1
I-2 手足口病疫苗開發近況………………………………………………………2
I-3 EV71與CVA16病毒特性……………………………………………………3
I-4 3Dpol RNA依賴型RNA聚合酶………………………………………………5
I-5 免疫佐劑………………………………………………………………………6
II 研究目的與實驗架構………………………………………………………………10
III 實驗方法與材料……………………………………………………………………11
III-1 3Dpol重組蛋白序列設計與聚合酶鏈鎖反應……………………………11
III-2 質體建構……………………………………………………………………11
III-3 大腸桿菌轉型作用…………………………………………………………12
III-4 3Dpol重組蛋白之表現與純化………………………………………………13
III-5 純化之3Dpol蛋白分析………………………………………………………15
III-6 3Cpro重組蛋白之表現與純化………………………………………………16
III-7 動物接種與攻毒測試………………………………………………………17
III-8 小鼠血清中和能力測試……………………………………………………18
III-9 脾臟細胞分離……………………………………………………………19
III-10 三明治酵素結合免疫分析法分析細胞激素之表達…..……...……………19
III-11 流式細胞染色……………………………………………………………….20
IV 實驗結果……………………………………………………………………………22
IV-1 大腸桿菌BL21表現重組3Dpol……………………………………………22
IV-2 單獨3Dpol對於CVA16之保護效果………………………………………22
IV-3 不同佐劑混合3Dpol對於CVA16之保護效果……………………………23
IV-4 不同佐劑混合3Dpol對於EV71之保護效果……………………………23
IV-5 3Dpol免疫成鼠後之血清中和能力…………………………………………24
IV-6 3Dpol免疫脾臟細胞後之細胞激素表現……………………………………24
IV-7 3Dpol對T細胞分化之影響…………………………………………………25
V 討論……………………………………………………………………………26
VI 未來規劃……………………………………………………………………30
VII 總結……………………………………………………………………………31
VIII 參考文獻…………………………………………………………………………32
附錄………………………………………………………………………………………62
1. Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR. 1999. An epidemic of enterovirus 71 infection in taiwan. Taiwan enterovirus epidemic working group. N Engl J Med. 341(13):929-935.
2. Lin TY, Twu SJ, Ho MS, Chang LY, Lee CY. 2003. Enterovirus 71 outbreaks, taiwan: Occurrence and recognition. Emerg Infect Dis. 9(3):291-293.
3. Wang JR, Tuan YC, Tsai HP, Yan JJ, Liu CC, Su IJ. 2002. Change of major genotype of enterovirus 71 in outbreaks of hand-foot-and-mouth disease in taiwan between 1998 and 2000. Journal of Clinical Microbiology. 40(1):10-15.
4. Yang F, Ren L, Xiong Z, Li J, Xiao Y, Zhao R, He Y, Bu G, Zhou S, Wang J et al. 2009. Enterovirus 71 outbreak in the people's republic of china in 2008. J Clin Microbiol. 47(7):2351-2352.
5. De W, Changwen K, Wei L, Monagin C, Jin Y, Cong M, Hanri Z, Jun S. 2011. A large outbreak of hand, foot, and mouth disease caused by ev71 and cav16 in guangdong, china, 2009. Arch Virol. 156(6):945-953.
6. Chua KB, Chua BH, Lee CS, Chem YK, Ismail N, Kiyu A, Kumarasamy V. 2007. Genetic diversity of enterovirus 71 isolated from cases of hand, foot and mouth disease in the 1997, 2000 and 2005 outbreaks, peninsular malaysia. The Malaysian journal of pathology. 29(2):69-78.
7. Chua KB, Kasri AR. 2011. Hand foot and mouth disease due to enterovirus 71 in malaysia. Virologica Sinica. 26(4):221-228.
8. AbuBakar S, Sam IC, Yusof J, Lim MK, Misbah S, MatRahim N, Hooi P-S. 2009. Enterovirus 71 outbreak, brunei. Emerging infectious diseases. 15(1):79-82.
9. Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, Chow VTK. 2010. The largest outbreak of hand; foot and mouth disease in singapore in 2008: The role of enterovirus 71 and coxsackievirus a strains. International Journal of Infectious Diseases. 14(12):e1076-e1081.
10. Buxbaum S, Berger A, Preiser W, Rabenau HF, Doerr HW. 2001. Enterovirus infections in germany: Comparative evaluation of different laboratory diagnostic methods. Infection. 29(3):138-142.
11. Mirand A, Henquell C, Archimbaud C, Ughetto S, Antona D, Bailly JL, Peigue-Lafeuille H. 2012. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus a6 and a10 infections in 2010, france: A large citywide, prospective observational study. Clinical Microbiology and Infection. 18(5):E110-E118.
12. Prager P, Nolan M, Andrews IP, Williams GD. 2003. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med. 4(3):377-381.
13. Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. 2007. Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in taiwan, 1998-2005. Pediatrics. 120(2):e244-252.
14. Zhang Y, Tan XJ, Wang HY, Yan DM, Zhu SL, Wang DY, Ji F, Wang XJ, Gao YJ, Chen L et al. 2009. An outbreak of hand, foot, and mouth disease associated with subgenotype c4 of human enterovirus 71 in shandong, china. J Clin Virol. 44(4):262-267.
15. Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, Clear D, del Sel S, Chieng CH, Tio PH, Cardosa MJ et al. 2009. Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in sarawak. BMC Infect Dis. 9:3.
16. Ooi MH, Wong SC, Podin Y, Akin W, del Sel S, Mohan A, Chieng CH, Perera D, Clear D, Wong D et al. 2007. Human enterovirus 71 disease in sarawak, malaysia: A prospective clinical, virological, and molecular epidemiological study. Clin Infect Dis. 44(5):646-656.
17. Perez-Velez CM, Anderson MS, Robinson CC, McFarland EJ, Nix WA, Pallansch MA, Oberste MS, Glode MP. 2007. Outbreak of neurologic enterovirus type 71 disease: A diagnostic challenge. Clin Infect Dis. 45(8):950-957.
18. Lu HK, Lin TY, Hsia SH, Chiu CH, Huang YC, Tsao KC, Chang LY. 2004. Prognostic implications of myoclonic jerk in children with enterovirus infection. J Microbiol Immunol Infect. 37(2):82-87.
19. Hosoya M, Sato M, Honzumi K, Katayose M, Kawasaki Y, Sakuma H, Kato K, Shimada Y, Ishiko H, Suzuki H. 2001. Association of nonpolio enteroviral infection in the central nervous system of children with febrile seizures. Pediatrics. 107(1):E12.
20. Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, Tan X, Wang L, Mao Q, Wu J et al. 2014. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in china. N Engl J Med. 370(9):818-828.
21. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, Zhang Y, Li Y, Mao Q, Wang J et al. 2014. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 370(9):829-837.
22. Zhu F-C, Meng F-Y, Li J-X, Li X-L, Mao Q-Y, Tao H, Zhang Y-T, Yao X, Chu K, Chen Q-H et al. 2013. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in china: A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 381(9882):2024-2032.
23. Cheng A, Fung CP, Liu CC, Lin YT, Tsai HY, Chang SC, Chou AH, Chang JY, Jiang RH, Hsieh YC et al. 2013. A phase i, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. Vaccine. 31(20):2471-2476.
24. Yan Q, Wu L, Chen L, Qin Y, Pan Z, Chen M. 2016. Vesicular stomatitis virus-based vaccines expressing ev71 virus-like particles elicit strong immune responses and protect newborn mice from lethal challenges. Vaccine. 34(35):4196-4204.
25. Wang X, Xiao X, Zhao M, Liu W, Pang L, Sun X, Cen S, Yang BB, Huang Y, Sheng W et al. 2016. Ev71 virus-like particles produced by co-expression of capsid proteins in yeast cells elicit humoral protective response against ev71 lethal challenge. BMC Res Notes. 9:42.
26. Chang H-W, Liu C-C, Lin M-H, Ho H-M, Yang Y-T, Chow Y-H, Chong P, Sia C. 2011. Generation of murine monoclonal antibodies which cross-neutralize human enterovirus genogroup b isolates. Journal of Virological Methods. 173(2):189-195.
27. Liu CC, Chou AH, Lien SP, Lin HY, Liu SJ, Chang JY, Guo MS, Chow YH, Yang WS, Chang KH et al. 2011. Identification and characterization of a cross-neutralization epitope of enterovirus 71. Vaccine. 29(26):4362-4372.
28. Xu L, He D, Li Z, Zheng J, Yang L, Yu M, Yu H, Chen Y, Que Y, Shih JWK et al. 2014. Protection against lethal enterovirus 71 challenge in mice by a recombinant vaccine candidate containing a broadly cross-neutralizing epitope within the vp2 ef loop. Theranostics. 4(5):498-513.
29. Jia Q, Ng Q, Chin W, Meng T, Chow VTK, Wang CI, Kwang J, He F. 2017. Effective in vivo therapeutic igg antibody against vp3 of enterovirus 71 with receptor-competing activity. Scientific reports. 7:46402.
30. Kirk K, Poh CL, Fecondo J, Pourianfar H, Shaw J, Grollo L. 2012. Cross-reactive neutralizing antibody epitopes against enterovirus 71 identified by an in silico approach. Vaccine. 30(49):7105-7110.
31. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. 2010. Virology, epidemiology, pathogenesis, and control of enterovirus 71. The Lancet Infectious Diseases. 10(11):778-790.
32. Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S. 2009. Scavenger receptor b2 is a cellular receptor for enterovirus 71. Nature Medicine. 15:798.
33. Ma HC, Liu Y, Wang C, Strauss M, Rehage N, Chen YH, Altan-Bonnet N, Hogle J, Wimmer E, Mueller S et al. 2014. An interaction between glutathione and the capsid is required for the morphogenesis of c-cluster enteroviruses. PLoS Pathog. 10(4):e1004052.
34. Rossmann MG, Arnold E, Erickson JW, Frankenberger EA, Griffith JP, Hecht H-J, Johnson JE, Kamer G, Luo M, Mosser AG et al. 1985. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature. 317(6033):145-153.
35. Ventoso I, MacMillan SE, Hershey JW, Carrasco L. 1998. Poliovirus 2a proteinase cleaves directly the eif-4g subunit of eif-4f complex. FEBS Lett. 435(1):79-83.
36. Gradi A, Svitkin YV, Imataka H, Sonenberg N. 1998. Proteolysis of human eukaryotic translation initiation factor eif4gii, but not eif4gi, coincides with the shutoff of host protein synthesis after poliovirus infection. Proceedings of the National Academy of Sciences of the United States of America. 95(19):11089-11094.
37. Rust RC, Landmann L, Gosert R, Tang BL, Hong W, Hauri HP, Egger D, Bienz K. 2001. Cellular copii proteins are involved in production of the vesicles that form the poliovirus replication complex. J Virol. 75(20):9808-9818.
38. Amineva SP, Aminev AG, Palmenberg AC, Gern JE. 2004. Rhinovirus 3c protease precursors 3cd and 3cd' localize to the nuclei of infected cells. J Gen Virol. 85(Pt 10):2969-2979.
39. Ypma-Wong M, Gillis Dewalt P, H. Johnson V, Lamb J, L. Semler B. 1988. Protein 3cd is the major poliovirus proteinase responsible for cleavage of the pi capsid precursor.
40. Flanegan JB, Petterson RF, Ambros V, Hewlett NJ, Baltimore D. 1977. Covalent linkage of a protein to a defined nucleotide sequence at the 5'-terminus of virion and replicative intermediate rnas of poliovirus. 74(3):961-965.
41. Sun Y, Wang Y, Shan C, Chen C, Xu P, Song M, Zhou H, Yang C, Xu W, Shi PY et al. 2012. Enterovirus 71 vpg uridylation uses a two-molecular mechanism of 3d polymerase. J Virol. 86(24):13662-13671.
42. Sun Y, Guo Y, Lou Z. 2014. Formation and working mechanism of the picornavirus vpg uridylylation complex. Curr Opin Virol. 9:24-30.
43. Bruenn JA. 2003. A structural and primary sequence comparison of the viral rna-dependent rna polymerases. Nucleic Acids Research. 31(7):1821-1829.
44. Surana P, Satchidanandam V, Nair DT. 2014. Rna-dependent rna polymerase of japanese encephalitis virus binds the initiator nucleotide gtp to form a mechanistically important pre-initiation state. Nucleic Acids Res. 42(4):2758-2773.
45. Elena SF, Sanjuan R. 2005. Adaptive value of high mutation rates of rna viruses: Separating causes from consequences. J Virol. 79(18):11555-11558.
46. Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina WM, Sam IC. 2012. Comparative genetic analysis of vp4, vp1 and 3d gene regions of enterovirus 71 and coxsackievirus a16 circulating in malaysia between 1997-2008. Tropical biomedicine. 29(3):451-466.
47. Hung H-C, Tseng C-P, Hsu JT-A, Chen T-C, Shih S-R, Yen K-J, Fang M-Y. 2010. Inhibition of enterovirus 71 replication and the viral 3d polymerase by aurintricarboxylic acid. Journal of Antimicrobial Chemotherapy. 65(4):676-683.
48. Chen T-C, Chang H-Y, Lin P-F, Chern J-H, Hsu JT-A, Chang C-Y, Shih S-R. 2009. Novel antiviral agent dtrip-22 targets rna-dependent rna polymerase of enterovirus 71. 53(7):2740-2747.
49. Wang W, Xiao F, Wan P, Pan P, Zhang Y, Liu F, Wu K, Liu Y, Wu J. 2017. Ev71 3d protein binds with nlrp3 and enhances the assembly of inflammasome complex. PLoS Pathog. 13(1):e1006123.
50. Jin YH, Kang B, Kim BS. 2009. Theiler's virus infection induces a predominant pathogenic cd4+ t cell response to rna polymerase in susceptible sjl/j mice. J Virol. 83(21):10981-10992.
51. Dang S, Gao N, Li Y, Li M, Wang X, Jia X, Zhai S, Zhang X, Liu J, Deng H et al. 2014. Dominant cd4-dependent rna-dependent rna polymerase-specific t-cell responses in children acutely infected with human enterovirus 71 and healthy adult controls. Immunology. 142(1):89-100.
52. Kerkvliet J, Zoecklein L, Papke L, Denic A, Bieber AJ, Pease LR, David CS, Rodriguez M. 2009. Transgenic expression of the 3d polymerase inhibits theiler's virus infection and demyelination. J Virol. 83(23):12279-12289.
53. Li Y, Yu J, Qi X, Yan H. 2019. Monoclonal antibody against ev71 3d(pol) inhibits the polymerase activity of rdrp and virus replication. BMC Immunol. 20(1):6.
54. Tsou YL, Lin YW, Shao HY, Yu SL, Wu SR, Lin HY, Liu CC, Huang C, Chong P, Chow YH. 2015. Recombinant adeno-vaccine expressing enterovirus 71-like particles against hand, foot, and mouth disease. PLoS Negl Trop Dis. 9(4):e0003692.
55. Siskind GW, Benacerraf B. 1969. Cell selection by antigen in the immune response. In: Dixon FJ, Kunkel HG, editors. Advances in immunology. Academic Press. p. 1-50.
56. Bonhoure F, Gaucheron J. 2006. Montanide isa 51 vg as adjuvant for human vaccines. 29(6):647-648.
57. Sanderson K, Scotland R, Lee P, Liu D, Groshen S, Snively J, Sian S, Nichol G, Davis T, Keler T et al. 2005. Autoimmunity in a phase i trial of a fully human anti-cytotoxic t-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide isa 51 for patients with resected stages iii and iv melanoma. J Clin Oncol. 23(4):741-750.
58. Slingluff CL, Petroni GR, Smolkin ME, Chianese-Bullock KA, Smith K, Murphy C, Galeassi N, Neese PY, Grosh WW, Nail CJ et al. 2010. Immunogenicity for cd8+ and cd4+ t cells of 2 formulations of an incomplete freund's adjuvant for multipeptide melanoma vaccines. J Immunother. 33(6):630-638.
59. Rao M, Alving CR. 2000. Delivery of lipids and liposomal proteins to the cytoplasm and golgi of antigen-presenting cells. Advanced Drug Delivery Reviews. 41(2):171-188.
60. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. 2002. Human tlr7 or tlr8 independently confer responsiveness to the antiviral compound r-848. Nat Immunol. 3(6):499.
61. Ahonen CL, Gibson SJ, Smith RM, Pederson LK, Lindh JM, Tomai MA, Vasilakos JP. 1999. Dendritic cell maturation and subsequent enhanced t-cell stimulation induced with the novel synthetic immune response modifier r-848. Cellular Immunology. 197(1):62-72.
62. Vasilakos JP, Smith RMA, Gibson SJ, Lindh JM, Pederson LK, Reiter MJ, Smith MH, Tomai MA. 2000. Adjuvant activities of immune response modifier r-848: Comparison with cpg odn. Cellular Immunology. 204(1):64-74.
63. Tomai MA, Gibson SJ, Imbertson LM, Miller RL, Myhre PE, Reiter MJ, Wagner TL, Tamulinas CB, Beaurline JM, Gerster JF et al. 1995. Immunomodulating and antiviral activities of the imidazoquinoline s-28463. Antiviral Research. 28(3):253-264.
64. Morefield GL, Sokolovska A, Jiang D, HogenEsch H, Robinson JP, Hem SL. 2005. Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine. 23(13):1588-1595.
65. Vajdy M, Selby M, Medina-Selby A, Coit D, Hall J, Tandeske L, Chien D, Hu C, Rosa D, Singh M et al. 2006. Hepatitis c virus polyprotein vaccine formulations capable of inducing broad antibody and cellular immune responses. J Gen Virol. 87(Pt 8):2253-2262.
66. Wack A, Baudner BC, Hilbert AK, Manini I, Nuti S, Tavarini S, Scheffczik H, Ugozzoli M, Singh M, Kazzaz J et al. 2008. Combination adjuvants for the induction of potent, long-lasting antibody and t-cell responses to influenza vaccine in mice. Vaccine. 26(4):552-561.
67. Hem SL, White JL. 1995. Structure and properties of aluminum-containing adjuvants. Pharmaceutical biotechnology. 6:249-276.
68. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. 2008. Crucial role for the nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 453:1122.
69. Franchi L, Nunez G. 2008. The nlrp3 inflammasome is critical for aluminium hydroxide-mediated il-1beta secretion but dispensable for adjuvant activity. Eur J Immunol. 38(8):2085-2089.
70. Volpi C, Fallarino F, Pallotta MT, Bianchi R, Vacca C, Belladonna ML, Orabona C, De Luca A, Boon L, Romani L et al. 2013. High doses of cpg oligodeoxynucleotides stimulate a tolerogenic tlr9-trif pathway. Nat Commun. 4:1852.
71. Hartmann G, Krieg AM. 2000. Mechanism and function of a newly identified cpg DNA motif in human primary b cells. J Immunol. 164(2):944-953.
72. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. 1997. Cpg oligodeoxynucleotides act as adjuvants that switch on t helper 1 (th1) immunity. The Journal of experimental medicine. 186(10):1623-1631.
73. Zhang Y, Yang E, Pu J, Liu L, Che Y, Wang J, Liao Y, Wang L, Ding D, Zhao T et al. 2014. The gene expression profile of peripheral blood mononuclear cells from ev71-infected rhesus infants and the significance in viral pathogenesis. PLoS One. 9(1):e83766.
連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔