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研究生:廖怡歆
研究生(外文):Yi-Shin Liao
論文名稱:奈米粒子攜帶介白素21治療慢性B型肝炎病毒感染
論文名稱(外文):IL-21-based nanoparticle delivery platform to treat chronic hepatitis B infection
指導教授:陶秘華陶秘華引用關係
指導教授(外文):Mi-Hua Tao
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
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:2020
畢業學年度:108
語文別:中文
論文頁數:80
中文關鍵詞:B型肝炎病毒聚乳酸甘醇酸奈米粒子介白素21腺病毒載體
外文關鍵詞:Hepatitis b virusPLGAnanoparticleinterleukin 21adenovirus vector
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目錄
致謝 i
中文摘要 ii
英文摘要 iv
目錄 vi
圖目錄 ix
表目錄 x
第一章、緒論 1
1.1 B型肝炎病毒(Hepatitis B virus, HBV) 1
1.1.1 B型肝炎病毒急性感染 1
1.1.2 B型肝炎病毒慢性感染 2
1.1.3慢性B型肝炎的免疫治療 3
1.2 B型肝炎病毒的免疫反應 3
1.2.1 T細胞免疫反應 3
1.2.2 B細胞免疫反應 4
1.3介白素21 5
1.3.1 IL-21的抗病毒能力 5
1.3.2 Ad/IL-21功能性治癒慢性B型肝炎小鼠模式 6
1.4奈米粒子 7
1.4.1聚乳酸甘醇酸奈米粒子 7
1.5實驗目的與設計 8
第二章、實驗材料與方法…………………………………………………………… 9
2.1實驗小鼠………………………………………………………… 9
2.2 pAAV/HBVp-質體製備………………………………… 9
2.3 重組腺相關病毒攜帶HBV聚合酶點突變基因(AAV/HBVp-)製備 9
2.4 病毒純化與定量 10
2.5 重組蛋白IL-21-Fc製備 10
2.6 聚乳酸甘醇酸奈米粒子攜帶IL-21-Fc (NP-rIL-21-Fc)製備 11
2.7 重組腺病毒載體攜帶介白素21 (Ad/IL-21)製備 12
2.8 IL-21生物活性分析 12
2.9 肝臟淋巴細胞分離 13
2.10 脾臟淋巴細胞分離 13
2.11 肝臟RNA萃取與基因表現定量分析 13
2.12 HBV血清和生化標誌分析 14
2.13 流式細胞儀分析 14
2.14 統計方法 15
第三章、實驗結果 16
3.1 重組介白素21-Fc融合蛋白(rIL-21-Fc)的質體構築與蛋白生產 16
3.2 rIL-21-Fc純化與定量 16
3.3 確認rIL-21-Fc的生物活性分析 17
3.4 奈米粒子攜帶重組蛋白IL-21-Fc (NP-rIL-21-Fc)的建構 18
3.5 探討NP-rIL-21-Fc對清除HBV的效果 19
3.5.1 確認sNP-rIL-21-Fc的生物活性 19
3.5.2 sNP-rIL-21-Fc治療可降低血清中HBsAg 20
3.5.3 sNP-rIL-21-Fc治療短暫降低血清中HBsAg 21
3.6調整PLGA-NP大小以改善HBV清除效果 22
3.6.1不同大小sNP-rIL-21-Fc的生物活性分析 22
3.6.2 以80nm sNP-rIL-21-Fc治療後對HBV小鼠血清中相關抗原表現量
影響 22
3.6.3 以150nm sNP-rIL-21-Fc治療後對HBV小鼠血清中相關抗原表現
量影響 23
3.7調整sNP-rIL-21-Fc治療劑量或治療時間以改善清除HBV效果 23
3.7.1 sNP-rIL-21-Fc治療時長對HBV小鼠血清中相關抗原影響 24
3.7.2 sNP-rIL-21-Fc治療劑量對HBV小鼠血清中相關抗原影響 24
3.8 探討腺病毒載體(Ad/Empty)在治療HBV小鼠過程中扮演的角色 25
3.8.1 Ad/Empty與sNP-rIL-21-Fc協同治療對HBV相關抗原表現量影響
25
3.8.2 Ad/Empty與NP-rIL-21-Fc協同治療對免疫細胞的影響 26
3.8.3 Ad/Empty與sNP-rIL-21-Fc協同治療對肝臟中細胞激素與趨化激素
影響 29
第四章、討論 31
4.1 PLGA-NP引發吞噬細胞產生吞噬作用 31
4.2 rIL-21-Fc附著在PLGA-NP表面上的方向性 32
4.3 Poly-dopamine潛在的負面影響 32
4.4 Anti-HBs抗體可能造成HBsAg短暫清除效果 33
4.5 腺病毒載體與先天性免疫的關係 34
4.6 PLGA-NP在慢性B型肝炎感染治療上的優勢 34
4.7未來展望 35
4.8 結論 35
第五章、參考文獻 37
第六章、實驗結果圖………… 52
第七章、附表 79

圖目錄
圖一、重組介白素21-Fc融合蛋白(rIL-21-Fc)的生產 52
圖二、重組介白素21-Fc融合蛋白(rIL-21-Fc)的純化與定量 53
圖三、rIL-21-Fc的生物活性分析 56
圖四、奈米粒子攜帶重組蛋白IL-21-Fc (NP-rIL-21-Fc)的製作流程 57
圖五、 奈米粒子表面攜帶重組蛋白IL-21-Fc (Surface-conjugated NP-rIL-21- Fc)
治療HBV小鼠能夠有效降低血清中HBsAg表現量 59
圖六、sNP-rIL-21-Fc治療短暫降低血清中HBsAg表現量 60
圖七、sNP-rIL-21-Fc大小對HBV小鼠血清中相關抗原表現量的影響 61
圖八、sNP-rIL-21-Fc治療次數與劑量對HBV小鼠血清中相關抗原表現量影響 64
圖九、腺病毒載體(Ad/Empty)與sNP-rIL-21-Fc合併治療對血清中HBV相關抗
原表現量的影響 67
圖十、腺病毒載體(Ad/Empty)和sNP-rIL-21-Fc對肝臟免疫細胞族群的影響 68
圖十一、腺病毒載體(Ad/Empty)和sNP-rIL-21-Fc對肝臟T細胞活化的影響 70
圖十二、腺病毒載體(Ad/Empty)和sNP-rIL-21-Fc對脾臟免疫細胞族群的影響 72
圖十三、腺病毒載體(Ad/Empty)和sNP-rIL-21-Fc對脾臟T細胞活化的影響 74
圖十四、腺病毒載體(Ad/Empty)合併sNP-rIL-21-Fc治療對脾臟germinal center
(GC) B細胞的影響 76
圖十五、腺病毒載體(Ad/Empty)合併sNP-rIL-21-Fc治療對肝臟內細胞激素
(cytokine)與趨化激素(chemokine)的影響 77

表目錄
表一、流式細胞儀分析所使用之螢光抗體 79
表二、NP-rIL-21-Fc治療慢性B型肝炎小鼠模式實驗統整 80
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