臺灣博碩士論文加值系統

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指導教授推薦書
論文口試委員會審定書
致 謝 iii
中文摘要 iv
Abstract vi
Contents viii
List of Figures xi
List of abbreviations xiii
Chapter 1: Introduction 1
1. 1 DNA vaccines 1
1.2 Granulocyte-macrophage colony-stimulating factor 3
1.3 Human papillomavirus 7
1.4 Prime-boost immunization 10
Chapter 2 Specific Objectives 12
Chapter 3: Materials and Methods 14
3.1 Construction of recombinant plasmids for mice 14
3.2 Cell lines and transfection 15
3.3 RNA extraction and quantitative real-time PCR 15
3.4 Western blotting 16
3.5 Measuring the secretion of GM-E7 and cytokines via ELISA 16
3.6 Binding ability of GM-E7 to LPS-treated Splenocytes 16
3.7 Mouse model 17
3.8 Preparation and in vitro stimulation of murine splenocytes 18
3.9 Cloning, expression, and purification of recombinant proteins 19
3.10 Measurement of HPV16 E7-specific IgG1/IgG2a antibodies by using ELISA 20
3.11 In vivo depletion of CD4+ or CD8+ T lymphocytes 20
3.12 Preparation of adenovirus 21
3.13 Immunization of mice using p-cGM-E7 plasmids and AdcGM-E7 within a DNA prime-Adenovirus boost regimen 22
3.14 Statistical analyses 22
Chapter 4 Results 24
4.1 Construction of cGM-CSF link to HPV 16 E7 plasmid 24
4.2 Analysis of E7 or GM-E7 protein expression via transfection 24
4.3 Estimating the cytokine secretion ability of GM-E7 and the binding ability of GM-E7 25
4.4 The linking of cGM-CSF to HPV16 E7 clearly elevated the expression of HPV 16 E7 25
4.5 Mice vaccinated with p-cGM-E7 showed enhanced immunosurveillance against TC-1 tumors compared with mice immunized with p-E7 26
4.6 Vaccinations with p-cGM-E7 elicited antigen-specific immune responses in CD4+ and CD8+ T cells 27
4.7 Cytokine production by splenocytes in DNA-vaccinated mice 28
4.8 Vaccination with p-cGM-E7 Fusion DNA does not significantly affect the generation of E7-specific antibodies compared to p-E7 28
4.9 Either CD8+ or CD4+ T cells are required to elicit the anti-tumor effects of p-cGM-E7 vaccinations in mice 29
4.10 Immunization with the DNA prime adenovirus boost that carried the cGM-E7 DNA provided superior immunosurveillance against TC-1 tumors compared to DNA prime boost with p-cGM-E7 or AdGFP 30
4.11 Cytokine production by splenocytes after DNA prime adenovirus boost 30
4.12 Immunization with the DNA prime adenovirus boost carrying cGM-E7 led to increased production of E7-specific antibodies compared to immunization with DNA or AdGFP 31
4.13 In vivo depletion of both CD4+ and CD8+ T cells influences the antitumor effects of the prime/boost strategy involving cGM-E7 31
Chapter 5 Discussion 33
Chapter 6 Conclusions 42
Reference 43
Figures 55



List of Figures
Figure 1. Construction of vaccine plasmids. 55
Figure 2. mRNA expressions of COS7 cell transfected with different recombinant plasmids were verified by RT-PCR. 56
Figure 3. Protein expression of E7 and GM-E7 was analysis by Western blotting. 57
Figure 4. The secretion of GM-E7 was detected by GM-CSF ELISA. 58
Figure 5. Binding of GM-CSF-E7 protein with LPS stimulated splenocytes. 59
Figure 6. Effect of cGM-CSF link to HPV16 E7 on expression and half-life of mRNA in transfection experiment. 60
Figure 7. Evaluation efficacy of the different DNA vaccine. 63
Figure 8. Assessment efficacy of the different vaccine. 65
Figure 9. Characterization of the E7-specific CD8+ T cell immune responses in mice immunized with DNA vaccines. 66
Figure 10. Flow cytometry analysis of IFN-γ-secreting E7-specific CD4+ T cells in mice. 68
Figure 11. Concentration of IFN-γ and IL-4 in supernatant restimulated with 10 ug/ml HPV16-E7 MHC class I or classs II peptide. 70
Figure 12. Expression and purification of HPV16 E7 in BL21(DE3). 71
Figure 13. E7-specific antibody responses in mice immunized with recombinant DNA vaccines. 73
Figure 14. Effect of lymphocyte subset depletions on the potency of the p-cGM-E7 DNA vaccine. 75
Figure 15. Evaluation efficacy of the DNA-prime/adenovirus boost immunization. 77
Figure 16. Assessment efficacy of the DNA-prime/Adenovirus regimen in different combination. 79
Figure 17. Concentration of IFN-γ and IL-4 from supernatant of DNA-prime/Adenovirus Boost immunization restimulated with HPV16 E7 10 ug/ml class I or classs II peptide. 80
Figure 18. Specific E7 antibody responses as detected by ELISA immunized with DNA/adenovirus prime boost strategy. 82
Figure 19. Effect of lymphocyte subset depletions on the potency of the DNA prime/adenovirus boost immunization. 84
Figure 20. Assessment of efficacy of the DNA-prime/adenovirus regimen in different T cell depletion. 86

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