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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57354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 | Chia-En Loh | en |
| dc.contributor.author | 羅家恩 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:42:48Z | - |
| dc.date.available | 2024-07-29 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-29 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57354 | - |
| dc.description.abstract | 原發性膽道硬化症（primary biliary cirrhosis；PBC）為一種肝臟特異性的自體免疫疾病，其病理特徵為淋巴細胞浸潤至門脈三角區且因膽管受到破壞導致膽汁的鬱積，隨著疾病的發展最終走向肝臟衰竭。患者週邊血液之TH1、TH17細胞及IFN-γ與IL-17均較正常人高。在此研究中我們利用本實驗室已建立之xenobiotic (2-OA-OVA)-induced PBC小鼠模式探討發炎細胞激素在PBC致病之角色。首先，我們確定2-OA-OVA/α-GalCer致敏小鼠的肝臟單核細胞經CD3/CD28 抗體刺激後會產生大量的IFN-γ與IL-17，而小鼠肝臟中IFN-γ與IL-17的基因表現量也有上升的情形。接著，我們利用腺相關病毒(adeno-associated virus；AAV)做為載體將不同的細胞激素基因送入小鼠體內，同時誘發小鼠產生PBC，觀察在不同細胞激素的發炎環境下對PBC的影響。我們的結果顯示在給予AAV-mIFN-γ的2-OA-OVA/α-GalCer致敏小鼠，其肝臟中NK細胞及NKT細胞數目顯著上升。此外在不使用α-GalCer的2-OA-OVA致敏小鼠給予AAV-mIFN-γ亦發現肝臟單核細胞數、NK細胞與NKT細胞數上升。給予AAV-mIL-17之2-OA-OVA/α-GalCer致敏小鼠肝臟門脈出現較嚴重的細胞浸潤，但並非淋巴細胞增加。相反地，給予AAV-mIL-4之2-OA-OVA/α-GalCer致敏小鼠，其肝臟單核細胞數明顯降低，但於肝臟切片卻發現肉芽腫數目增加。因此，我們推測IFN-γ能夠活化先天性免疫細胞促使肝臟得以破除免疫耐受性，IL-17則可能造成非淋巴細胞浸潤於門脈，相反地IL-4則有可能透過將TH1免疫反應誘導成TH2反應而降低浸潤至肝臟的免疫細胞數及其活化程度。 | zh_TW |
| dc.description.abstract | Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by slowly progressive non-suppurative cholangitis caused by immune-mediated destruction of intrahepatic bile ducts. Lymphocytes were recruited to the portal triad accompanied with the presence of antimitochondrial antibodies (AMAs) in the serum of PBC patients, the higher level of proinflammatory cytokines such as IFN-γ can also be detected in serum samples. The frequencies of autoreactive CD4+ T cells, CD8+ T cells and natural killer T (NKT) cells are higher in the liver which suggests a role for the cellular immunity that remain to be determined. CD4+ T cells can be divided into four subsets with distinct functions, including T helper (TH) 1, TH2, TH17 and regulatory T cells. By using a unique compound 2-OA-OVA, accompanied with α-GalCer injection, we established PBC-like syndrome in mice in order to study the cytokines milieus effects on the pathogenesis of PBC. Adeno-associated virus (AAV)-based vector was used to overexpress different cytokines in liver as it only induced minor response in vivo. We found IFN-γ significantly increased NK cells and NKT cells in the liver of 2-OA-OVA/α-GalCer immunized mice. To prevent the IFN-γ production from α-GalCer stimulation, we immunized the mice with 2-OA-OVA without α-GalCer and found that, IFN-γ was still able to induce NK and NKT cells infiltrating to liver and caused activation of NK cells. In contrast to IFN-γ, IL-17 caused the more severe pathological pattern which was not induced by hepatic lymphocytes. Interestingly, IL-4 decreased much of the T cells and NKT cells in liver of immunized mice albeit there were increased granulomas in the liver. We concluded that IFN-γ can induce activation of NK and NKT cells to break immune tolerance when presented antigen by antigen-preseting cells. IL-17 may cause non-lymphoid infiltrating in portal triad, while IL-4 may regulate the inflammatory response by skewing the TH1 responses to TH2 responses. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:42:48Z (GMT). No. of bitstreams: 1 ntu-103-R01424003-1.pdf: 3450829 bytes, checksum: a59fc7ee515c4c652cf6edd9ce2793da (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 致謝 1
中文摘要 ii Abstract iii 縮寫對照表 v 第一章 研究背景 1 1.1. 原發性膽道硬化症（Primary biliary cirrhosis；PBC） 1 1.1.1. 臨床診斷 1 1.1.2. 自體抗體 1 1.1.3. PBC之病因 2 1.1.4. 病理特徵 4 1.1.5. 先天性免疫反應 4 1.1.6. 後天性免疫反應與細胞性免疫反應 5 1.1.7. Xenobiotic-induced PBC小鼠模式 5 1.2. 輔助型T細胞 (T helper cell, TH cell) 及細胞激素在原發性膽道硬化症之角色 6 1.2.1. 輔助型T細胞 6 1.2.2. 細胞激素與自體免疫疾病 7 1.2.3. TH1及TH17與PBC 9 1.3. Adeno-associated virus (AAV) 10 1.3.1. AAV-DJ Helper Free Bicistronic Expression System (GFP) 11 1.4. 研究動機與目的 11 第二章 材料與方法 12 2.1. AAV製備 12 2.2. 病毒之純化與濃縮 12 2.3. 病毒的定量 13 2.4 利用pAAV-mIFN-γ、pAAV-mIL-4及pAAV-mIL-17轉染AD293細胞 14 2.5. 實驗用小鼠 14 2.6. 2-OA-OVA/α-GalCer induced PBC小鼠模式 14 2.7. 以AAV施打PBC小鼠 15 2.8. 小鼠肝臟灌流與肝臟單核細胞分離 15 2.9. 以流式細胞儀FACS Calibur(BD)分析肝臟分離單核細胞表面抗原 15 2.10. 肝臟單核細胞體外培養 16 2.11. 血清樣品之收集 16 2.12. 血清中細胞激素之測定 17 2.13. 以ELISA測量PBC小鼠血清中anti-mPDC-E2 IgG及IgM 17 2.14. 肝臟病理切片製作 18 2.15 細胞RNA萃取、反轉錄及real-time PCR 19 2.16. 繪圖及統計分析 19 第三章 實驗結果 20 3.1. 利用Xenobiotic（2-OA-OVA/α-GalCer）誘發C57BL/6小鼠產生原發性膽道硬化症 20 3.2. PBC小鼠肝臟單核細胞經刺激後產生發炎性細胞激素IFN-γ及IL-17 21 3.3. 我們所建構出的帶有不同細胞激素基因的質體可成功將細胞激素分泌至上清液中，且具有正常的功能 21 3.3.1. pAAV-mIFN-γ之表現 21 3.3.2. pAAV-mIL-4之表現 22 3.3.3. pAAV-mIL-17之表現 22 3.4. AAV以尾靜脈注射入小鼠體內後，可在小鼠肝臟表現 22 3.5. 致敏前施打帶有不同細胞激素基因之AAV，各組別間的肝臟單核細胞總數未見明顯的改變 23 3.6. 給予AAV-mIL-4之小鼠肝臟中CD4+ 與CD8+ T細胞減少，T細胞與NK細胞活化的百分比下降 23 3.7. 小鼠經致敏後全數產生anti-PDC-E2 IgM及IgG，但給予AAV-mIL-17的小鼠之IgG效價降低 24 3.8. 給予AAV-mIL-17之致敏小鼠其肝臟細胞浸潤的情形增加 24 3.9. Naive小鼠給予α-GalCer之後，血清中IFN-γ與IL-4濃度升高 25 3.10. 給於AAV-mIFN-γ之PBC小鼠肝臟單核細胞總數增加，NK細胞與NKT細胞數也有顯著性增加，且NK細胞活化百分比上升 25 第四章 結論與討論 26 附圖 32 參考文獻 56 附錄 65 | |
| dc.language.iso | zh-TW | |
| dc.subject | 原發性膽道硬化症 | zh_TW |
| dc.subject | IFN-γ | zh_TW |
| dc.subject | IL-17 | zh_TW |
| dc.subject | IL-4 | zh_TW |
| dc.subject | AAV | zh_TW |
| dc.subject | 先天性免疫反應 | zh_TW |
| dc.subject | IFN-γ | en |
| dc.subject | primary biliary cirrhosis | en |
| dc.subject | innate immunity | en |
| dc.subject | AAV | en |
| dc.subject | IL-17 | en |
| dc.subject | IL-4 | en |
| dc.title | 輔助型T細胞相關細胞激素調控原發性膽道硬化症之研究 | zh_TW |
| dc.title | Study of Helper T-associated Cytokines on the Regulation of Primary Biliary Cirrhosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊雅倩(Ya-Chien Yang),沈家瑞(Chia-Rui Shen),吳慧琳(Hui-Lin Wu) | |
| dc.subject.keyword | 原發性膽道硬化症,IFN-γ,IL-17,IL-4,AAV,先天性免疫反應, | zh_TW |
| dc.subject.keyword | primary biliary cirrhosis,IFN-γ,IL-4,IL-17,AAV,innate immunity, | en |
| dc.relation.page | 72 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-29 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 未授權公開取用 | 3.37 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。