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研究生:林美秀
研究生(外文):Mei-Hsiu Lin
論文名稱:不同微脂粒組成份包覆新城病毒(NDV)點鼻劑型疫苗之研究
論文名稱(外文):The Research of Different Liposomes-encapsulated NDV Vaccine by Nasal Administration for Chickens
指導教授:劉得任劉得任引用關係
指導教授(外文):Der-Zen Liu
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:生物醫學材料研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:97
中文關鍵詞:微脂粒新城病毒聚甘露醣
外文關鍵詞:LiposomeNewcastle disease virusMannanchickenphosphatidylserinevaccineintranasal
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本研究以半包覆式微脂粒疫苗之點鼻劑型,包裹新城病毒活毒LaSota株(Newcastle disease virus, NDV),利用不同組成分的微脂粒包覆新城病毒及降低疫苗施予之劑量,同時也設計一組在微脂粒疫苗載體表面修飾上覆蓋聚甘露醣(Mannan)形成「靶向式微脂粒疫苗」,期許能夠快速被黏膜下層之抗原呈現細胞所辨別進而胞吞以引發下一步之免疫反應。本實驗著重於血清及鼻黏膜抗體的產生以及攻毒試驗,觀測抗體生成的情況(抗體IgG、IgA、IgM)、組織切片以及攻毒後的試驗結果。結果發現,利用給予一次或兩次疫苗微脂粒包覆新城病毒隻疫苗,發現施予兩次疫苗的實驗可有效引發雞隻在上呼吸道之抗體IgA與IgG產生,以及血清中有較高的IgG。攻毒結果指出在低劑量微脂粒疫苗的免疫情況下,Lip-NDV-1/5、Man-Lip- NDV-1/5與Man-Lip-NDV-1/10這三組亦能達到良好的保護效果。組織切片結果發現,攻毒前,微脂粒疫苗組別之組織切片中其可減緩新城病毒對雞隻肺臟鬱積;攻毒後,微脂粒疫苗之PS-Lip-NDV、SA-Lip-NDV和Man-Lip-NDV之組別相較於NDV-only組,發現微脂粒包覆新城病毒之疫苗有降低肺臟細胞壞死缺失之現象。因此,利用微脂粒包覆新城病毒之疫苗藉由點鼻的方式給予可引發較好的黏膜免疫的抗體產生以、良好的保護效果且能有效降低新城病毒強毒株對雞隻的傷害。
Newcastle disease virus, live LaSota strain, was encapsulated with semi- liposome vaccine and administrated by intranasal route. This study utilized different phospholipid compounds of liposomes to encapsulate Newcastle disease virus and decreased the dosage of liposomal vaccine. When coated with mannan on the surface of liposomes as “targeting liposome”, liposomal vaccines expect to recognize by antigen presenting cell in the nasal submucosa. This study focuses on the production of the serum and nasal mucosal antibody, tissue pathology, and the protection after challenging. The result of the test through primary or boost vaccination by liposome-encapsulated Newcastle disease virus indicated that the boost vaccination (two times) can produce antibody in chicken serum. Therefore, the result of protective efficacy after virulence challenge show that Lip-NDV-1/5, Man-Lip-NDV-1/5, and Man-Lip-NDV-1/10 groups can provide better protection than others. The results of histology, liposomal vaccine groups can reduce lung congestion before challenge; however, after the virulence NDV challenge, liposomal vaccines (ex: PS-Lip-NDV, SA-Lip-NDV, and Man-Lip-NDV) can reduce lung necrosis and loss than NDV-only vaccine group. In conclusion, utilize liposome-encapsulated Newcastle disease virus vaccine can induce mucosal immunity, have better protection efficacy, and reduce the tissue damage than that of NDV-only vaccines by intranasal route.
目錄
第一章 緒論...................................................1
§1-1 疫苗演進及劑型介紹.........................................1
•1-1-1 現今疫苗的分類.....................................2
•1-1-2 免疫劑型的分類.....................................3
§1-2 黏膜免疫系統簡介...........................................3
§1-3 新城病毒簡介...............................................5
§1-4 微脂粒包覆與制放技術........................................5
第二章 微脂粒簡介...............................................7
§2-1 微脂粒的結構與組成........................................8
§2-2 微脂粒的分類...............................................11
§2-3 微脂粒基本的製備方法........................................12
§2-4 微脂粒的性質...............................................12
§2-5 微脂粒的穩定度.............................................13
§2-6 微脂粒與佐劑的關係..........................................14
第三章 微脂粒新城病毒(Newcastle disease virus, NDV)疫苗中主要材料性質介紹18
§3-1 新城病毒介紹...............................................18
•3-1-1 新城病毒的特性及抗原毒性分類.......................18
•3-1-2 感染與傳播方式............................................20
•3-1-3 臨床症狀.........................................21
•3-1-4 肉眼病變.................................................21
•3-1-1 組織病理病變......................................21
§3-2 微脂粒成份介紹..............................................24
•3-2-1 磷脂質...................................................24
•3-2-2 膽固醇...................................................25
§3-3 聚甘露醣介紹................................................28
•3-3-1 聚甘露醣的來源與免疫功效...................................28
•3-3-2 聚甘露醣的生物活性.........................................29
•3-3-3 聚甘露醣結合蛋白...........................................31
第四章 研究動機與實驗目的.........................................33
第五章 實驗設備與實驗方法.........................................39
§5-1 實驗材料....................................................39
§5-2 實驗藥品....................................................39
§5-3 實驗儀器與設備...............................................40
•5-3-1 粒徑與界面電位分析儀..................................40
•5-3-2 減壓濃縮機...........................................42
•5-3-3 其他設備儀器.........................................42
•5-3-4 實驗動物及操作工具....................................43
§5-4 實驗方法.....................................................43
•5-4-1 溶液配製.............................................43
•5-4-2 微脂粒製備...........................................45
•5-4-3 粒徑分析.............................................46
•5-4-4 界面電位測定.........................................46
•5-4-5 包覆率分析...........................................47
•5-4-6 利用雞胚胎蛋複製新城病毒...............................47
•5-4-7 動物實驗.............................................47
•5-4-8 攻毒試驗.............................................48
•5-4-9 抗體分析(血液、鼻腔沖洗液).............................49
•5-4-10 血球凝集試驗HA test...................................49
•5-4-11 血球抑制凝集試驗HI test...............................50
第六章 結果與討論..................................................51
§6-1 粒徑分析......................................................51
§6-2 界面電位分析..................................................52
§6-3 包覆率分析....................................................53
§6-4 動物實驗分析..................................................54
•6-4-1 血清抗體分析.........................................54
•6-4-2 鼻腔沖洗液抗體分析....................................59
•6-4-3 血清抗體力價(HI tier)與攻毒試驗分析....................61
•6-4-4 組織切片.............................................64
第七章 結論........................................................75
第八章 未來展望....................................................76
第九章 參考文獻....................................................77
圖表索引
【圖1-1】M cell與黏膜免疫之引發.......................................5
【圖1-2】微脂粒利用親疏水性的特性將藥物包覆之簡說圖......................6
【圖2-1】磷脂質基本結構圖 ...........................................8
【圖2-2】常見磷脂質的化學結構圖.......................................10
【圖2-3】微脂粒應用上分類方式.........................................11
【圖2-4】微脂粒的融合作用.............................................13
【圖3-1】新城病毒結構................................................20
【圖3-2】磷脂醯膽鹼..................................................24
【圖3-3】硬脂胺化學結構式.............................................25
【圖3-4】膽固醇分子之結構圖...........................................26
【圖3-5】膽固醇在微脂粒雙層膜中所佔據的位置.............................27
【圖3-6】聚甘露醣結合蛋白辨識甘露醣圖示................................28
【圖3-7】MBP在動物體之分佈的樹枝圖....................................32
【圖3-8】雞隻的Mannan-Bing Lectin(MBL)結構圖.........................32
【圖4-1】研究架構...................................................35
【圖4-2】雞隻中樞免疫器官示意圖.......................................36
【圖4-3】黏膜免疫細胞分佈............................................38
【圖4-4】黏膜免疫引發系統性免疫之假設路徑圖............................38
【圖5-1】界面電位示意圖..............................................42
【圖5-2】粒徑與界面電位分析儀.........................................42
【圖5-3】免疫時間設計圖示............................................48
【圖6-1】不同組成份之微脂粒新城病毒疫苗粒徑分布情況.....................52
【圖6-2】不同組成份之微脂粒新城病毒疫苗界面電位分析......................53
【圖6-3】不同組成份之微脂粒新城病毒疫苗包覆率分析.......................54
【圖6-4】原倍劑量單次免疫之血清中抗體IgG分析...........................55
【圖6-5】原倍劑量兩次免疫之血清中抗體IgG分析...........................57
【圖6-6】原倍劑量兩次免疫之血清中抗體IgA分析...........................57
【圖6-7】原倍劑量兩次免疫之血清中抗體IgM分析...........................58
【圖6-8】低倍劑量單次免疫之血清中抗體IgG分析...........................59
【圖6-9】原倍劑量兩次免疫之鼻腔沖洗液中抗體IgA、IgG、IgM分析............60
【圖6-10】未攻毒之免疫雞隻肝臟組織切片................................67
【圖6-11】攻毒之免疫雞隻肝臟組織切片..................................68
【圖6-12】未攻毒之免疫雞隻肺臟組織切片................................69
【圖6-13】攻毒之免疫雞隻肺臟組織切片..................................70
【圖6-14】未攻毒之免疫雞隻脾臟組織切片................................71
【圖6-15】攻毒之免疫雞隻脾臟組織切片..................................72
【圖6-16】未攻毒之免疫雞隻氣管組織切片................................73
【圖6-17】攻毒之免疫雞隻氣管組織切片..................................74
【表2-1】疫苗佐劑的選擇.............................................15
【表4-1】不活化疫苗與活毒要苗之比較...................................34
【表6-1】低劑量單次免疫,HI titer及攻毒試驗結果........................62
【表6-2】原劑量單次免疫,HI titer及攻毒試驗結果........................63
【表6-3】組織切片分析結果............................................66
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