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系統識別號 U0007-1008201113434700
論文名稱(中文) 應用新型微脂粒佐劑開發雞隻黏膜疫苗
論文名稱(英文) Devolepment of Bioadhesive Liposomes As a Novel Adjuvant for Chicken
校院名稱 臺北醫學大學
系所名稱(中) 牙醫學系碩博士班
系所名稱(英) School of Dentistry
學年度 99
學期 2
出版年 100
研究生(中文) 邱垂章
研究生(英文) Chwei-Jang Chiou
學號 D204095004
學位類別 博士
語文別 中文
口試日期 2011-07-28
論文頁數 111頁
口試委員 指導教授-劉得任
委員-詹東榮
委員-鄧明中
委員-梁友志
委員-侯文琪
中文關鍵字 微脂粒  禽流感  佐劑  黏膜免疫 
英文關鍵字 liposome  avian influenza  adjuvant  mucosal immunity 
學科別分類
中文摘要 微脂粒(liposome)以其生物膜(biomembrane)模式的特性,可做為刺激特定抗原黏膜免疫的疫苗佐劑。微脂粒應用於細菌類、寄生蟲類、和病毒類等抗原載體系統已被確認極具潛力。黏膜免疫的方法簡便且安全,有效的黏膜疫苗可以誘導局部黏膜組織的免疫反應,進而阻止病原的入侵,還可引起全身性體液免疫反應(humoral immune responses),可針對抗原產生特異性抗體,使動物獲得保護力。家禽流行性感冒(avian influenza)簡稱禽流感,主要感染禽類,造成禽類不同程度的呼吸道疾病、緊迫及產蛋率下降,甚至死亡等,疫情嚴重時可造成雞場大規模損失。而現有商品化死毒疫苗大多為多劑量劑型,疫苗的接種方式需要逐隻免疫注射,除了耗費人力、容易發生微生物汙染而對防疫人員有潛在的危害風險。因此,本研究應用多層型微脂粒(multilamellar liposome)作為抗原載體(vector),嘗試製備具生物黏膜吸附性(mucoadhesion)、具免疫調節(immunomodulation)活性成分CpG-ODN及以半乳糖基(galactocsyl)修飾之具有標靶性(targeting)功能等之多層微脂粒複合物(complex)的黏膜疫苗佐劑。其免疫調節成分預期可促進黏膜免疫反應,而生物黏膜吸附性成分可延長疫苗於黏膜之滯留以延緩抗原釋放。並配合微脂粒多層釋放行為促進抗原在黏膜上免疫反應,而具靶向傳遞性之微脂粒,使微脂粒表面可以展示出半乳糖基,期望能夠在黏膜與血清中產生較多的S-IgA及IgG抗體,同時刺激細胞後產生較佳的發炎反應,增加細胞攝入單醣標靶微脂粒疫苗。
先將磷脂質(phospholipids)與膽固醇(cholesterol)依適當比例混合,並經由超音波震盪後再包覆製成複合多層式微脂粒。經雷射光粒徑分析儀分析測得之平均粒徑範圍為1.3-3.9 µm,抗原包覆率為38%-45%。體外抗原釋放率實驗證實此一複合多層型態微脂粒經凍乾(freeze drying)後處理後其粒徑、抗原包覆率、與抗原釋放率皆與未凍乾前無明顯差異,此結果對於未來應用於疫苗商品化及保存運送將有很大的幫助。動物實驗方面,為探討生物性黏膜吸附微脂粒應用於鼻腔免疫之功效。本研究所用之生物性黏膜吸附性微脂粒是以銀耳多醣(tremella)或是三仙膠(xanthan gum)所開發而成。藉由雞隻做為標的動物進行黏膜局部感染,以評估此種生物性黏膜吸附性微脂粒流感疫苗是否能促進疫苗之效果。(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium,MTS)細胞毒性試驗顯示銀耳多醣、三仙膠或微脂粒對雞隻的脾臟巨噬細胞是無毒的。使用低劑量(200 μL)之生物黏膜吸附性微脂粒流感疫苗免疫之雞隻,有顯著較高的黏膜與血清抗體力價。此外,將微脂粒混合低黏度生物黏膜吸附凝膠,比混合高黏度之生物黏膜吸附凝膠,經鼻腔免疫後有更好的抗體反應。這表示低黏度凝膠混合微脂粒更適合應用於鼻腔黏膜免疫,且免疫後可在黏膜誘發較高的S-IgA,以及血清中較高的中和免疫球蛋白IgG力價。以含有CpG-ODN之複合多層微脂粒複合物包覆由行政院農委會家畜衛生試驗所提供不活化之H5N3禽流感病毒抗原,經鼻黏膜免疫途徑給予四週齡無特定病原種SPF來亨氏雞進行動物效力實驗。結果顯示複合多層微脂粒不論在血清中之IgA及IgG,甚至鼻黏膜之分泌型S-IgA的產量,皆明顯較單純多層微脂粒疫苗高。在半乳糖基標靶性微脂粒研究方面,結果顯示與一般微脂粒相較,含galactosyl lipid微脂粒較能刺激脾臟巨噬細胞產生顯著NO濃度。機制研究結果顯示galactosyl lipid微脂粒可能經由活化NF-κB 路徑來刺激巨噬細胞產生NO,進而刺激後續之免疫反應。其結果亦證實含galactosyl lipid的微脂粒具有較高的免疫促進性,也較易進入細胞內活化免疫機制。綜合上述,本研究應用具有多重功能性之多層複合式微脂粒複合物於雞禽流感鼻黏膜疫苗之開發,實驗結果顯示所開發的具有多重功能性之多層複合式微脂粒複合物可作為有效、安全且穩定的黏膜佐劑,可支持未來進一步田間試驗對抗禽流感的感染。
英文摘要 Liposomes based on biomembrane models have been widely studied and used as effective mucosal adjuvants to stimulate mucosal immune responses against specific antigens. Liposomes have been considered as a potential delivery system for vaccine application against a variety of antigens, including bacteria, parasites and viruses. Mucosal vaccination represents a safe and convenient route to effectively induce local immune responses in mucosa tissue, as well as systemic humoral immune responses producing antigen-specific antibodies in protection of animals from pathogenic attack. Avian influenza (AI) outbreaks may cause a massive economic loss in chicken farms due to a high mortality rate and a significant decrease in both growth rate and egg production in infected chicken. Current AI vaccines, mainly made from inactivated viruses, are multi-dose parenteral formulations requiring individually injection to chickens; this immunization regimen is time consuming with a potential risk of microbial containmination that may jeoparadize workers who conduct the vaccination in fields. Therefore, a more convenient and safer dosing regimen for AI vaccination is of importance. The present study employed mutilamellar liposome as an antigen vector with functions of mucoadhesion, immunomodulation and targeting. The aim is to develop novel mutilamellar liposome complexes as effective mucosal adjuvants for inactivated AI virus. It is expected that the mucosal immune responses will be enhanced by the slow-releasing effect of mucoadhesive components and the mucosal stimulating activity of immunomodulators such as CpG-ODN in the formulated liposome-based vaccines. In addition, galactosyl-conjugated liposomes were expected to enhance the production of secretory immunoglobulin A (S-IgA) and IgG antibodies in the mucus and serum, respectively, due to an increased uptake of liposomes by immune cells.
Multilamellar liposomes based on proper ratios of phospholipids and cholesterol were prepared by ultrasound sonication. The size distribution of liposomes ranged from 1.3-3.9 µm. The percentage of antigen encapsulation was 38% to 45%. The in vitro antigen-release profile of an entrapped marker antigen from different liposomal formulations was studied. The results showed that the size distribution, antigen encapsulation percentage, and antigen-release profile of multilamellar liposome complex with/without freeze drying were comparable. In animal experiments, 4-week-old specific pathogen free white Leghorn chickens were used as the animal model. Inactivated H5N3 virus was kindly provided by Animal Health Research Institute, Council of the Agriculture. Bioadhesive liposomes were developed using tremella (T) or xanthan gum (XG) as the bioadhesive polysaccharides. The present study evaluated whether nasal delivery of bioadhesive liposomal influenza vaccines could improve vaccine effectiveness. Results from the 3-(4,5-dimethylthiazol-2-yl)- 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cytotoxicity assays demonstrated that T, XG and liposomes were not toxic to chicken splenic macrophages. Chickens immunized with a low dose (200 μL) of bioadhesive liposomal influenza vaccines exhibited significantly higher mucosal and serum antibody titers. In addition, liposomes formulated with a low-viscosity bioadhesive gel used for nasal delivery elicited a superior antibody response compared to liposomes mixed with a high-viscosity gel. These results suggest that a low-viscosity gel mixed with liposomes is more suitable for nasal delivery and that the immunized chickens produce greater levels of mucosal S-IgA and serum IgG after two vaccinations. Moreover, chicken intranasally vaccinated with multilamellar liposome complex with CpG-ODN significantly increased levels of nasal S-IgA and serum IgA and IgG as compared to controls. Compared to the conventional liposomes, liposomes with galactosyl ligands showed a greater effect to induce the production of nitric oxide (NO) by macrophages. Mechanistic studies further demonstrated that liposomes based on galactosyl-lipid formuation were capable of stimulating macrophage production of NO via NF-κB activation. These results suggest that galactosyl-liposomes have higher immunostimulating properties and increased uptake by cells to enhance immune responses. Taken together, the multilamellar liposome complexes with various functions developed in the present study were shown effective, safe, stable and easy to apply, substantiating a potential as effective mucosal adjuvants for chicken AI mucosal vaccines, thereby supporting their further application in the field against AI infection.
論文目次 中文摘要……………………………………………………………………………i
英文摘要……………………………………………………………………………..iii
誌謝…………………………………………………………………………………vi
頁次…………………………………………………………………………………viii
圖次…………………………………………………………………………………..xii
表次………………………………………………………………………………….xiv
縮寫表……………………………………………………………………………….xv
第一章 前言……………………………………………………....…………………1
第二章 文獻探討……………………………………………………………………7
2-1 家禽流行性感冒病毒歷史背景…………………………………..…..7
2-2 家禽流行性感冒病毒之特性…………………………………………8
2-2-1 AI病毒的特性與分類……………………………………...8
2-2-2 AI病毒的物理特性………………………………………10
2-2-3 感染AI病毒的臨床症狀…………………………………10
2-3 疫苗的種類………………………………………………………..…11
2-4 黏膜免疫系統之簡介………………………………………………..12
2-4-1 黏膜免疫系統………..……………………………………12
2-4-2 黏膜表面的免疫反應……………………………………13
2-4-3 呼吸道的免疫防禦系統…………………………………..15
2-4-4 分泌型免疫球蛋白A……………………………………16
2-5 雞隻免疫系統簡介…………………………………………………..17
2-5-1 非特異性免疫反應………………………………………17
2-5-2 特異性免疫反應…………………………………………18
2-6 佐劑…………………………………………………………………..22
2-6-1 佐劑的作用機轉…………………………………………22
2-6-2 佐劑和抗原載體系統……………………………………23
2-6-3 黏膜佐劑之開發…………………………………………25
2-7 微脂粒………………………………………………………………..26
2-7-1 微脂粒的性質……………………………………………26
2-7-2 微脂粒在體內的吸收與清除……………………………27
2-7-3 微脂粒之免疫佐劑活性…………………………………28
2-7-4微脂粒應用於黏膜免疫……………………………………..32
2-8 CpG-ODN之免疫促進……………………………………….……33
2-9 醣類接枝微脂粒……………………………………………………..35
2-10 一氧化氮……………………………………………………………..36
第三章 材料與方法………………………………………………………………38
3-1 病毒………………………………………………………………….38
3-2 藥品………………………………………………………………….38
3-3 微脂粒之製備………………………………………………………38
3-3-1 多層微脂粒的製備…………………………………………...38
3-3-2 複合多層微脂粒的製備……………………………………...39
3-3-3 醣類接枝微脂粒之方法……………………………………...39
3-4 包覆率分析…………………………………………………………..40
3-5 粒徑與介面Zeta電位之分析………………………………………..40
3-6 微脂粒型態分析……………………………………………………..41
3-7 釋放實驗……………………………………………………………..41
3-8 複合多層微脂粒冷凍乾燥劑型製備………………………………..41
3-9 銀耳多醣的萃取……………………………………………………..42
3-10 黏膜吸附性多醣黏度測試………………………………………….42
3-11 實驗動物與分組…………………………………………………….42
3-11-1 免疫接種時間表與劑量…………………………………..42
3-11-2 免疫流程…………………………………………………..43
3-11-3 樣本的收集………………………………………………..43
3-12 抗體力價檢測………………………………………………………..44
3-12-1 酵素免疫連結分析法……………………………………..44
3-12-2 血球抑制凝集試驗……………………………………….45
3-13 血清和鼻腔分泌物中之抗體ELISA測定…………………………45
3-14 細胞的分離和培養………………………………………………….45
3-15 體外細胞毒性試驗………………………………………………….46
3-16 亞硝酸鹽測定試驗………………………………………………….46
3-17 統計分析…………………………………………………………….47
第四章 結果………………………………………………………………………48
4-1 生物吸附性微脂粒之物理化學性質………………………………..48
4-2 生物吸附性微脂粒之體外細胞活性檢測…………………………..48
4-3 疫苗免疫後之抗體反應……………………………………………..49
4-4 生物吸附性材料混合微脂粒誘導抗體反應………………………49
4-5 生物吸附性材料之黏度對抗體反應之影響……………………...49
4-6 複合多層微脂粒物理性質之分析…………………………………..50
4-7 複合多層微脂粒物的抗原釋放情形………………………………..50
4-8 冷凍乾燥複合多層微脂粒劑型之分析……………………………..51
4-9 抗原力價及血球抑制凝集試驗…………………………………….51
4-10 醣類接枝多層微脂粒劑型之體外細胞活性檢測分析…………….52
4-11 加入抑制劑後其NO生成量………………………………………..53
第五章 討論………………………………………………………………………69
5-1 具生物黏膜吸附性微脂粒複合物…………………………………..69
5-2 具免疫促進活性CpG-ODN多層微脂粒複合物…………………73
5-3 具有標靶性微脂粒複合物…………………………………………..75
第六章 結論………………………………………………………………………77
第七章 未來展望…………………………………………………………………78
第八章 參考文獻…………………………………………………………………79
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