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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 莊雅惠 | |
| dc.contributor.author | Yu-Chi Chen | en |
| dc.contributor.author | 陳幼淇 | zh_TW |
| dc.date.accessioned | 2021-06-16T22:58:23Z | - |
| dc.date.available | 2022-12-31 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-08 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64744 | - |
| dc.description.abstract | 原發性膽道硬化症(Primary biliary cirrhosis ; PBC)為一種具肝臟特異性的自體免疫疾病，患者肝臟內細小膽管慢性破壞，導致膽汁鬱積、膽管及門脈周圍發炎，連帶肝細胞也遭到破壞，產生肝纖維化，最後肝硬化。臨床研究發現，PBC病人肝臟內的自體抗原特異性T細胞(autoantigen specific T cell)比週邊血多且肝臟組織有CD8 T細胞浸潤。本實驗室先前發表以外源生質物(Xenobiotics：2-OA-BSA)及α-GalCer誘發正常基因小鼠產生PBC的小鼠模式，此PBC小鼠肝臟CD8 T細胞數量高於正常小鼠，並有肝臟發炎、肝纖維化等疾病特徵，與臨床病人情形相符。在此研究中我們探討 CD8 T細胞在PBC的病理變化的角色。
首先，我們確認2-OA-BSA/α-GalCer誘發PBC的小鼠模式中肝臟的conventional T細胞及其中的CD8 T細胞數量增加，並且發現肝臟單核細胞分泌IFN-γ及IL-17增加、T細胞浸潤於肝臟門脈區。將PBC小鼠的T細胞後天轉移至正常小鼠中，部分接受轉移的小鼠可見血清中抗粒線體抗體(AMA)上升、肝臟單核細胞分泌IFN-γ增加，相似於在2-OA-BSA/α-GalCer誘發的PBC小鼠中看到的現象。接著我們分析PBC小鼠的T細胞子分群分泌IFN-γ能力，發現CD8 T細胞分泌IFN-γ的比例高於CD4 T細胞，進一步分析肝臟單核細胞中CD8 T細胞活化情形，可見CD69+比例和FasL及granzyme B表現量升高，顯示細胞被活化且具有細胞毒殺能力。將PBC小鼠的CD8 T細胞後天轉移至正常小鼠中，結果接受轉移的小鼠血清中AMA明顯上升、肝臟單核細胞分泌IFN-γ增加，與T細胞轉移實驗結果相仿。 接著，我們利用2-OA-BSA/α-GalCer分別誘發正常基因小鼠與CD8基因剔除(CD8-/-)小鼠產生PBC反應，結果發現缺乏CD8 T細胞的小鼠仍會被誘發產生PBC： AMA產生、肝臟單核細胞分泌IFN-γ，以及肝臟發炎、門脈三角淋巴球浸潤、膽道破壞及肝纖維化等病理變化，其門脈浸潤的情形比正常基因小鼠更為嚴重。進一步探討CD8-/-小鼠受2-OA-BSA/α-GalCer誘發產生PBC的原因，我們發現致敏後CD8-/-小鼠的肝臟γδ T細胞大量增加，且會分泌 IFN-γ並表現FasL及Granzyme B，可能具有取代CD8 T細胞使CD8-/-小鼠產生PBC的能力。 綜合以上實驗數據，我們認為CD8 T細胞在2-OA-BSA/α-GalCer誘發的PBC小鼠模式中具有細胞毒殺性，可以直接或間接促使肝臟發炎、膽管破壞，逐漸發展至肝纖維化。然而在缺乏CD8 T細胞的情形下，γδT細胞可能會受2-OA-BSA/α-GalCer誘發，取代CD8 T細胞使小鼠產生PBC。 | zh_TW |
| dc.description.abstract | Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease with progressive destruction of intrahepatic bile ducts, decreased bile flow and destruction of hepatocytes, leading to scarring, fibrosis and then cirrhosis. In PBC patients, the number of autoantigen specific T cells in the liver is higher than in peripheral blood and CD8 T cells infiltration in the portal tracts is also present. Our lab previously established a murine model of PBC with xenobiotics (2-OA-BSA) /α-GalCer immunization The 2-OA-BSA/α-GalCer injected mice had an increased number of liver CD8 T cell numbers and developed PBC-like features such as liver lymphoid infiltration, portal inflammation, and fibrosis. In this study, we investigated the role of CD8 T cells in the pathogenesis of PBC.
First, we confirmed that the number of conventional T cells and CD8 T cells were increased in 2-OA-BSA /α-GalCer induced PBC mice and T cells infiltration in portal tracts were also observed. In addition, the secretion of IFN-γ and IL-17 from liver mononuclear cells (LMNCs) of PBC mice was increased. After adoptive transferring of T cells from PBC mice, increased serum levels of AMAs and secretion of IFN-γ of LMNC in recipients was noted. Further, we demonstrated that the frequency of IFN-γproducing liver CD8 T cells was higher than that of liver CD4 T cells. Moreover, CD8 T cells from PBC mice expressed higher CD69, FasL and granzyme B than in naive mice, suggesting that the CD8 T cells in PBC mice are activated and can be cytotoxic. We then adoptively transferred CD8 T cells from PBC mice into naive mice. Increased serum levels of AMAs and secretion of IFN-γ from LMNC of recipients were also obeserved, which was similar to the results of mice transferred with total T cells. However, CD8 deficient (CD8-/-) mice immunized with 2-OA-BSA /α-GalCer developed AMAs in serum, IFN-γ secretion of LMNC, liver portal infiltration and fibrosis like the characteristics in wild type mice. Additionally, we found γδ T cells were expanded in CD8-/- PBC mice and possessed cytotoxic potential, suggesting γδ T cells might be pathogenic in CD8-/- PBC mice. In conclusion, our data suggested that CD8 T cells in 2-OA-BSA /α-GalCer induced PBC mice were hyperreactive and cytotoxic, and that these cells directly or indirectly induced lesions of PBC. In addition, γδ T cells might replace the pathogenesis role of CD8 T cells when CD8 T cells are deficient. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T22:58:23Z (GMT). No. of bitstreams: 1 ntu-101-R99424019-1.pdf: 6733606 bytes, checksum: e5c719fc79502dd58c36107b2d8bef10 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii Abbreviation v 圖表目錄 xi 第一章 總論 1 1.1. 原發性膽道硬化症(Primary biliary cirrhosis ; PBC) 1 1.2. 組織病理學特徵與疾病病程分期 1 1.3. 血清免疫學特徵 1 1.4. 發病原因與致病因子 2 1.4.1. 自體抗體反應與自體反應B細胞 (Auto-antibody response and auto-reactive B cell) 2 1.4.2. 自體抗原特異性T細胞(Autoantigen-specific T cell) 3 1.4.3. 遺傳與環境因子 3 1.5. PBC的小鼠模式 3 1.5.1. 2-OA-BSA/α-GalCer induced PBC小鼠模式 4 第二章 探討CD8 T細胞在原發性膽道硬化症之角色 5 1. 研究背景 5 1.1. CD8 T 細胞 5 1.2. 自體抗原特異性T細胞的活化 5 1.3. CD8 T 細胞與自體免疫疾病 5 1.3.1. CD8 T細胞與多發性硬化症 6 1.3.2. CD8 T細胞與胰島素第一型糖尿病 7 1.3.3. CD8 T細胞與類風濕性關節炎 7 1.3.4. CD8 T 細胞與原發性膽道硬化症 8 2. 研究目的 10 3. 材料與方法 11 3.1. 實驗用小鼠 11 3.2. 2-OA-BSA/α-GalCer induced PBC 小鼠模式 11 3.3. 小鼠肝臟灌流與肝臟單核細胞分離 11 3.4. 以流式細胞儀分析肝臟單核細胞表面抗原 12 3.5. 細胞激素分泌分析 13 3.6. 小鼠肝臟組織切片製備 13 3.7. 免疫組織化學染色 13 3.8. 後天轉殖(adoptive transfer) T 細胞 14 3.9. 脾臟單核細胞分離 15 3.10. 肝臟單核細胞細胞內抗原分析 15 3.11. 血清樣品之收集 16 3.12. 血清中抗粒線體抗體效價測定 16 3.13. 繪圖與統計分析 17 4. 實驗結果 18 4.1. 以 2-OA-BSA/α-GalCer致敏之PBC小鼠的肝臟T細胞及CD8 T細胞數量增加且分泌高量IFN-γ及IL-17 18 4.2. 以 2-OA-BSA/α-GalCer致敏之PBC小鼠的肝臟門脈區有T細胞浸潤，其中包含CD8 T細胞 18 4.3. 將 2-OA-BSA/α-GalCer致敏之PBC小鼠的T細胞轉移至正常小鼠，可以促使接受轉移小鼠血清中AMAs效價升高，且其肝臟單核細胞可分泌較高量IFN-γ 19 4.4. 以 2-OA-BSA/α-GalCer致敏之PBC小鼠的CD8 T細胞表現IFN-γ的比例高於CD4 T細胞，且CD69+比例、FasL及Granzyme B表現量高於Naive小鼠。 20 4.5. 將 2-OA-BSA/α-GalCer致敏之PBC小鼠的CD8 T細胞轉移至正常小鼠，可以促使小鼠血清中AMAs效價升高，且肝臟單核細胞可分泌較高量IFN-γ及IL-17 20 4.6. 缺乏CD8 T細胞的小鼠仍會受 2-OA-BSA/α-GalCer誘發產生PBC，但肝臟單核細胞分泌IFN-γ及IL-17的量較低 21 4.6.1. 以 2-OA-BSA/α-GalCer誘發PBC之WT與CD8-/- 小鼠血清中均可以測得AMAs，且兩者間並無差異 22 4.6.2. 以 2-OA-BSA/α-GalCer誘發PBC之CD8-/- 小鼠的肝臟T細胞仍會分泌IFN-γ及IL-17，但分泌量低於WT小鼠 22 4.6.3. 以 2-OA-BSA/α-GalCer誘發PBC之CD8-/- 小鼠的肝臟門脈有淋巴球浸潤，且發炎程度高於WT PBC小鼠，但肝臟纖維化程度沒有顯著差異。 22 4.7. 12週後，以 2-OA-BSA/α-GalCer誘發產生PBC之CD8-/-小鼠肝臟單核細胞總數與WT PBC小鼠沒有顯著差異，但其中 γδ T細胞數增加 23 4.8. 12週後，以 2-OA-BSA/α-GalCer誘發產生PBC之CD8-/-小鼠肝臟γδ T細胞數較Naive之CD8-/-小鼠高，且升高比例大於WT小鼠。 24 4.9. 以 2-OA-BSA/α-GalCer誘發產生PBC之CD8-/-小鼠肝臟γδ T細胞會表現FasL、IFN-γ及Granzyme B。 24 5.結論與討論 26 第三章 圖 31 參考文獻 52 附錄 59 | |
| dc.language.iso | zh-TW | |
| dc.subject | γδ T細胞 | zh_TW |
| dc.subject | CD8 T細胞 | zh_TW |
| dc.subject | 2-OA-BSA | zh_TW |
| dc.subject | 原發性膽道硬化症 | zh_TW |
| dc.subject | Primary Biliary Cirrhosis | en |
| dc.subject | CD8 T cell | en |
| dc.subject | 2-OA-BSA | en |
| dc.subject | gamma delta T cell | en |
| dc.title | 以外源生質物誘發之小鼠模式探討CD8 T細胞在原發性膽道硬化症之角色 | zh_TW |
| dc.title | Study on the Role of CD8 T Cells in Xenobiotic Induced Primary Biliary Cirrhosis Murine Model | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陶秘華,孫昭玲,楊宏志 | |
| dc.subject.keyword | 原發性膽道硬化症,2-OA-BSA,CD8 T細胞,γδ T細胞, | zh_TW |
| dc.subject.keyword | Primary Biliary Cirrhosis,CD8 T cell,2-OA-BSA,gamma delta T cell, | en |
| dc.relation.page | 62 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-08-09 | |
| 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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