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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 莊雅惠(Ya-Hui Chuang) | |
dc.contributor.author | Chun-Wen Chan | en |
dc.contributor.author | 詹竣文 | zh_TW |
dc.date.accessioned | 2021-06-16T06:35:05Z | - |
dc.date.available | 2025-07-23 | |
dc.date.copyright | 2020-09-01 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-07-23 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57106 | - |
dc.description.abstract | 原發性膽汁性膽管炎 (Primary biliary cholangitis;PBC) 為一具有肝臟特異性的慢性自體免疫疾病,患者的肝內膽管受自體免疫細胞的攻擊與浸潤,造成膽汁淤積在肝臟導致肝損傷,且隨著疾病發展至肝纖維化、肝硬化等。近期研究發現Th17細胞可能與PBC疾病晚期的患者大多發展至肝纖維化有關,但其中機制尚未清楚,因此,本研究探討Th17分泌之細胞激素IL-17A、 IL-17F及IL-21在PBC扮演的角色跟作用機轉。我們使用實驗室長期建立的2-OA-OVA分子誘發PBC之小鼠模式,藉助腺相關病毒載體 (Adeno-associated virus;AAV) 攜帶IL-17A、IL-17F與IL-21基因以感染小鼠,探討上述細胞激素對於PBC的影響。首先,我們發現給予AAV-IL-21的小鼠,疾病發炎情形明顯變嚴重且肝臟浸潤細胞數升高,主要增加的細胞為CD8 T細胞,其數目、活化情形與毒殺能力皆上升。我們也觀察到IL-21具有促進肝臟內記憶T細胞生成的效果。此外,IL-21也加劇疾病晚期肝纖維化病程。另一方面,PBC小鼠給予AAV-IL-17A後不影響疾病的發炎情形,但可觀察到肝臟內浸潤的CD11b+ Ly6G+ 多核性白血球數量增加,以及Th1免疫反應降低的現象。最後,疾病小鼠給予AAV-IL-17F也不影響PBC的病程。綜合以上結果,顯示IL-21在PBC扮演促進發炎的角色,反之IL-17A與IL-17F則無顯著促發炎效果。 | zh_TW |
dc.description.abstract | Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by intrahepatic bile duct injuries, resulting in fibrosis, cirrhosis, and eventually liver failure. Recent studies have showed that the imbalance towards Th17 in advanced PBC may contribute to liver fibrosis, but the mechanism is unclear. Therefore, we investigated whether Th17 secreting cytokines including IL-17A, IL-17F and IL-21 could exacerbate disease severity and liver fibrosis. We treated mice with 2-OA conjugated OVA to induce PBC. We also injected adeno-associated virus (AAV) as a vector to overexpress cytokines in mouse liver. Our results showed that PBC mice administered with AAV-IL-21 enhanced liver inflammation and cell infiltration. CD8+ T cells were significantly increased and accompanied with increased activation and cytotoxic function in AAV-IL-21-treated mice. We found IL-21 boosted memory T cells expansion in the liver. Additionally, IL-21 aggravated the course of liver fibrosis. AAV-IL-17A administration didn’t enhance liver inflammation in PBC mice. However, increased CD11b+ Ly6G+ cells and decreased Th1 cells in the liver were observed. Lastly, AAV-IL-17F administration didn’t affect disease severity either. In conclusion, IL-21 exacerbated liver inflammation and fibrosis in our PBC model, but IL-17A and IL-17F did not. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T06:35:05Z (GMT). No. of bitstreams: 1 U0001-2207202017222700.pdf: 3626640 bytes, checksum: 996daf403fa4eeb38bb246ba062e4d54 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 致謝 i 中文摘要 ii Abstract iii 中英文縮寫對照表 iv 目錄 v 圖目錄 vii 第一章 研究背景 1 1.1 原發性膽汁性膽管炎 (Primary biliary cholangitis;PBC) 1 1.1.1 臨床診斷與疾病分期 1 1.1.2 治療方式 1 1.1.3 自體抗體 2 1.1.4 PBC之發病原因 2 1.1.5 PBC之免疫反應 3 1.1.6 Xenobiotic-induced PBC之小鼠模式 5 1.2 T helper 17 cells (Th17) 5 1.2.1 IL-17家族 5 1.2.2 IL-17A與自體免疫疾病 7 1.2.3 IL-17F與自體免疫疾病 7 1.2.4 IL-21 8 1.2.5 IL-21與自體免疫疾病 8 1.3 Th17分泌之細胞激素與PBC關係 9 1.4 腺相關病毒 (Adeno-associated virus;AAV) 10 1.4.1 AAV-DJ Helper Free Bicistronic Expression System (GFP) 10 1.5 研究動機與目的 11 第二章 實驗材料與方法 12 2.1 實驗用小鼠 12 2.2 以2OA-OVA誘發PBC之小鼠模式 12 2.3 AAV攜帶Th17細胞激素之製備 12 2.4 AAV純化與濃縮 13 2.5 AAV定量 13 2.6 AAV施打小鼠 13 2.7 小鼠犧牲及病理切片之製作 14 2.8 Masson’s Trichrome 染色 14 2.9 免疫螢光染色與定量分析 14 2.10 分離小鼠肝臟內白血球 (Liver Leukocytes) 15 2.11 細胞表面染色與流式細胞儀分析 15 2.12 偵測細胞激素與胞內染色 (Intracellular staining;ICS) 16 2.13 以Cytospin方式觀察肝臟白血球型態 16 2.14 小鼠血清之分離 16 2.15 測定小鼠血清內之細胞激素 17 2.16 測定小鼠血清內之抗PDC-E2抗體 17 2.17 肝臟組織萃取RNA與反轉錄成cDNA 18 2.18 聚合酶連鎖反應 (Polymerase chain reaction,PCR) 18 2.19 即時定量聚合酶連鎖反應 (Quantitative real-time PCR,qRT-PCR) 18 2.20 以西方墨點法分析肝臟α-SMA 19 2.21 繪圖及統計分析 19 第三章 實驗結果 20 3.1 確認pAAV-IL-17A、pAAV-IL-17F及pAAV-IL-21攜帶之細胞激素具有生物性功能,並比較IL-17A及IL-17F之能力差異 20 3.2 PBC小鼠給予AAV攜帶Th17細胞激素於小鼠體內表現之能力 20 3.3 PBC小鼠給予AAV-IL-21促進肝臟發炎 21 3.4 PBC小鼠給予AAV-IL-21增加肝臟內CD8 T細胞數量、活化及細胞毒殺能力 22 3.5 PBC小鼠給予AAV-IL-21增加肝臟內記憶T細胞 22 3.6 PBC小鼠給予AAV-IL-17A增加肝臟內CD11b+ Ly6G+ 細胞浸潤,且表現較高量CXCL1 23 3.7 給予AAV-IL-17A之PBC小鼠肝臟內Th1細胞百分比降低 23 3.8 PBC小鼠給予AAV-IL-21促進肝纖維化病程 24 第四章 結論與討論 25 圖 30 參考文獻 52 附錄 65 | |
dc.language.iso | zh-TW | |
dc.title | 探討IL-17及IL-21於自體免疫性膽管炎的免疫調控作用 | zh_TW |
dc.title | Effects of IL-17 and IL-21 on Murine Autoimmune Cholangitis | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蘇剛毅(Kang-Yi Su),吳慧琳(Hui-Lin Wu),鄒協成(Shey-Cherng Tzou) | |
dc.subject.keyword | 原發性膽汁性膽管炎,介白素17A,介白素17F,介白素21,腺相關病毒, | zh_TW |
dc.subject.keyword | Primary biliary cholangitis,IL-17A,IL-17F,IL-21,AAV, | en |
dc.relation.page | 73 | |
dc.identifier.doi | 10.6342/NTU202001746 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-07-24 | |
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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