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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 莊雅惠 | |
| dc.contributor.author | Yun-Ning Chang | en |
| dc.contributor.author | 張芸寧 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:26:06Z | - |
| dc.date.available | 2025-08-05 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-05 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53592 | - |
| dc.description.abstract | 原發性膽道硬化症 (Primary biliary cirrhosis，PBC) 是一種慢性肝臟自體免疫疾病，它是由於免疫系統攻擊肝內小膽管造成非化膿性發炎、損壞及膽汁鬱積的情況，最終導致肝纖維化及肝硬化發生，臨床上有三分之一病人對於唯一核准之臨床用藥-ursodeoxycholic acid (UDCA) 不具感受性，顯示目前對於發展新型藥物之迫切與需要。IL-22屬於IL-10 cytokine family，它是一個對抗外來病原菌感染、促進組織修復及維持組織完整之細胞激素，在免疫反應調控上也扮演重要角色。在許多發炎反應中，IL-22具有抑制發炎及修復之效果，而在多種肝臟發炎及自體免疫疾病模式中，IL-22更被指出具有保護作用。先前研究指出AAV (Adeno-associated virus) 本身不具致病性，且AAV vector能有效感染不同細胞並且長期表現所攜帶之目標基因，目前在動物模式及臨床試驗中以AAV vector作為基因治療載體皆顯示不錯之成效。本實驗室先前研究將小鼠誘發PBC前以尾靜脈注射方式給予3 x 107 TU AAV-mIL-22，發現可有效減緩門脈浸潤及纖維化現象，顯示IL-22在PBC疾病中具有保護性之免疫調節作用。本研究探討以AAV攜帶IL-22基因在PBC疾病中之治療效果。我們使用2-OA-OVA搭配α-GalCer致敏小鼠產生PBC症狀，並於致敏後第三周將9 x 107 TU AAV-mIL-22以尾靜脈注射方式給予PBC小鼠，並於第十周犧牲觀察發炎及纖維化相關之肝臟病理、mRNA、及單核球變化。實驗結果顯示給予9 x 107 TU AAV-mIL-22可降低浸潤到肝臟單核球數目，並減少發炎相關細胞激素 (IFN-γ及TNF-α)、chemokines (CXCL10及CXCL16)、及纖維化相關基因 (collagen I及collagen III) 之mRNA表現，以減緩門脈區發炎及纖維化現象。因此AAV-mIL-22可有效減緩PBC疾病以達治療之效果，未來期許可作為治療PBC疾病之臨床用藥。 | zh_TW |
| dc.description.abstract | Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by immune-mediated destruction of small-size intrahepatic bile ducts, leading to non-suppurative cholangitis, liver fibrosis and cirrhosis. There are one-third of PBC patients showing inadequate biochemical response to single-licensed therapy- ursodeoxycholic acid (UDCA). Awareness of unmet need has demonstrated the urgency and demand of development of new therapeutic treatment to PBC disease. IL-22, a member of the IL-10 cytokine family, is associated with antimicrobial defense, tissue repair and integrity as well as immune regulation. IL-22 is important with anti-inflammatory response and tissue repair in many inflammatory diseases. IL-22 serves as a protective role in a variety of liver injury and autoimmune diseases. Adeno-associated virus (AAV) vectors can efficiently infect a variety of cells and maintain long-term gene expression and has not been associated with pathology. AAV-mediated gene therapy has shown success in many animal disease models and clinical trials. Our previous study showed that mice injected with 3 x 107 TU of AAV-mIL-22 before initiation of PBC had decreased infiltration of immune cells and fibrosis in liver portal triads of 2-OA-OVA/α-GalCer immunized mice, suggesting that IL-22 played a protective role in PBC disease. In this study, we investigated the therapeutic effects of AAV-mIL-22 in PBC disease. 9 x 107 TU AAV-mIL-22 were injected to 2-OA-OVA/α-GalCer immunized mice at week 3 post immunization and PBC features including liver pathology, inflammatory cytokines and fibrosis-related proteins, liver mononuclear cells infiltration were examined at week 10. Our results demonstrated that administration of 9 x 107 TU AAV-mIL-22 efficiently reduced liver mononuclear cells infiltration and mRNA expressions of inflammatory-related cytokines (IFN-γ and TNF-α), chemokines (CXCL10 and CXCL16) and fibrosis-related proteins (collagen I and collagen III). In conclusion, AAV-mIL-22 treatment could efficiently reduce PBC disease and could be a promising treatment to PBC in the future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:26:06Z (GMT). No. of bitstreams: 1 ntu-104-R02424011-1.pdf: 4762922 bytes, checksum: 9c6ef8437dc52b8bc65361c8f474adc8 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 致謝 l 摘要 ll Abstract lll 縮寫對照表 V 目錄 Vl 圖目錄 lX 第一章 研究背景 1 1.1 肝臟及免疫系統 1 1.1.1 原發性膽道硬化症 (Primary biliary cirrhosis，PBC) 1 1.1.2 PBC之免疫反應 2 1.1.2.1 膽道上皮細胞 2 1.1.2.2 先天性免疫細胞 2 1.1.2.3 後天性免疫細胞 3 1.1.3 PBC之致病因子 3 1.1.4 PBC之治療藥物 4 1.1.5 Xenobiotic–induced PBC之小鼠模式 4 1.2 IL-22及IL-22 receptor complex 5 1.2.1 IL-22之訊息傳遞 5 1.2.2 IL-22之分泌細胞與作用細胞 6 1.2.3 IL‑22–IL‑22R1 system之生理功能 6 1.2.4 IL‑22–IL‑22R1 system與發炎反應之關係 7 1.2.5 IL‑22–IL‑22R1 system在肝臟之功能 7 1.2.6 IL‑22–IL‑22R1 system與原發性膽道硬化症 8 1.3 腺相關病毒Adeno-associated virus (AAV) 及其基因 8 1.3.1 AAV生活史及其感染 9 1.3.2 AAV作為基因表現載體 9 1.3.3 AAV基因表現載體之臨床試驗 10 1.4 研究目的 11 第二章 實驗材料與方法 12 2.1 AAV組裝 12 2.2 AAV純化 12 2.3 AAV濃縮及定量 13 2.4 實驗用小鼠 13 2.5 Xenobiotics (2-OA-OVA) 誘發PBC小鼠模式及AAV注射 14 2.6 血清樣本收集 14 2.7 小鼠肝臟之灌流與病理切片之製作 14 2.8 小鼠肝臟單核細胞的純化 15 2.9 流式細胞儀 (flow cytometry) 分析細胞表面抗原 15 2.10 利用ELISA測定血清中的細胞激素 16 2.11 以ELISA測定PBC小鼠血清中的anti-mPDC-E2 IgM及IgG 16 2.12 組織及細胞RNA之萃取 17 2.13 RNA反轉錄成cDNA 17 2.14 以即時定量反轉錄聚合酶連鎖反應偵測特定基因之mRNA表現 17 2.15 Portal inflammation分析及計算 18 2.16 繪圖與統計分析 18 第三章 實驗結果 19 3.1 以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠血清內IL-22的濃度 19 3.2 第三周以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠其血清內anti - mitochondrial Ab (anti-PDC-E2 IgM及IgG) 的表現 19 3.3 第三周以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠其肝臟發炎細 胞浸潤的情況及發炎細胞激素基因的表現 20 3.4 第三周以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠其肝臟纖維化 的情況及纖維化相關基因的表現 20 3.5 第三周以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠其肝臟內單核 球總數、淋巴球總數及其subsets 21 3.6 第三周以尾靜脈注射高濃度AAV-mIL-22之PBC鼠其肝臟內 chemokines的表現 21 3.7 第五周以尾靜脈注射高濃度AAV-mIL-22之PBC鼠其血清內anti - mitochondrial Ab (anti-PDC-E2 IgM及IgG) 的表現 22 3.8 第五周以尾靜脈注射高濃度AAV-mIL-22之PBC鼠其肝臟發炎細胞 浸潤的情況及發炎細胞激素基因的表現 22 3.9 第五周以尾靜脈注射高濃度AAV-mIL-22之PBC鼠其肝臟肝臟纖維 化的情況及纖維化相關基因的表現 22 4.0 第五周以尾靜脈注射高濃度AAV-mIL-22之PBC鼠其肝臟內單核球 總數、淋巴球總數及其subsets 23 第四章 討論 24 附圖 31 參考文獻 55 附錄 65 圖一、PBC小鼠模式及第三周AAV注射之實驗流程 32 圖二、PBC小鼠模式及第五周AAV注射之實驗流程 33 圖三、以尾靜脈注射不同濃度AAV-mIL-22之PBC鼠血清內表現IL-22之情形 34 圖四、以2-OA-OVA/α-GalCer之PBC鼠第二周血清內AMA表現 35 圖五、第三周以尾靜脈注射3 x 107 TU AAV-mIL-22之PBC鼠第十周血清AMA表現 36 圖六、第三周以尾靜脈注射3 x 107 TU AAV-mIL-22之PBC鼠肝臟發炎情形 37 圖七、第三周以尾靜脈注射3 x 107 TU AAV-mIL-22之PBC鼠肝臟纖維化情形 38 圖八、第三周以尾靜脈注射3 x 107 TU AAV-mIL-22之PBC鼠肝臟單核球細胞總數及其亞群 39 圖九、第三周以尾靜脈注射3 x 107 TU AAV-mIL-22之PBC鼠肝臟中T細胞之亞群 40 圖十、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠第十周血清AMA表現 41 圖十一、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟發炎情形 42 圖十二、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟纖維化情形 43 圖十三、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟單核球細胞總數及其亞群 44 圖十四、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟中T細胞及CD4 T細胞之亞群 45 圖十五、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟中T cells及其亞群之活化情形 46 圖十六、第三周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟中相關chemokines基因之表現情形 47 圖十七、以2-OA-OVA/α-GalCer之PBC鼠第四周血清內AMA表現 48 圖十八、第五周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠第十周血清AMA表現 49 圖十九、第五周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟發炎情形 50 圖二十、第五周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟纖維化情形 51 圖二十一、第五周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟單核球細胞總數及其亞群 52 圖二十二、第五周以尾靜脈注射9 x 107 TU AAV-mIL-22之PBC鼠肝臟中T細胞之亞群 53 圖二十三、AAV-mIL-22減緩PBC疾病之可能免疫機轉模式 54 | |
| dc.language.iso | zh-TW | |
| dc.subject | 肝硬化 | zh_TW |
| dc.subject | 原發性膽道硬化症 | zh_TW |
| dc.subject | 細胞介質素22 | zh_TW |
| dc.subject | 腺相關病毒 | zh_TW |
| dc.subject | 肝纖維化 | zh_TW |
| dc.subject | Primary biliary cirrhosis | en |
| dc.subject | liver cirrhosis | en |
| dc.subject | liver fibrosis | en |
| dc.subject | Adeno-associated virus | en |
| dc.subject | IL-22 | en |
| dc.title | 腺相關病毒攜帶Interleukin-22基因在原發性膽道硬化症之治療效果 | zh_TW |
| dc.title | Therapeutic Effects of IL-22 Expressing Adeno-Associated Virus on Primary Biliary Cirrhosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 劉旻禕,莊雅婷,陳雅雯 | |
| dc.subject.keyword | 原發性膽道硬化症,細胞介質素22,腺相關病毒,肝纖維化,肝硬化, | zh_TW |
| dc.subject.keyword | Primary biliary cirrhosis,IL-22,Adeno-associated virus,liver fibrosis,liver cirrhosis, | en |
| dc.relation.page | 67 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-08-05 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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