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研究生:謝錦桐
研究生(外文):Chin-Tung Hsieh
論文名稱:肝臟浸潤淋巴細胞的活化與召集
論文名稱(外文):Activation and Recruitment of Liver-Infiltrating Lymphocytes
指導教授:許秉寧許秉寧引用關係
指導教授(外文):Hsu, Ping-Ning
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:89
中文關鍵詞:腫瘤浸潤淋巴球肝臟浸潤淋巴球趨化激素受器CXCR6趨化激素CXCL16肝細胞癌刀豆素引發肝炎
外文關鍵詞:tumor-infiltrating lymphocyteliver-infiltrating lymphocyteCXCR6CXCL16hepatocellular carcinomaCon A induced hepatitis
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摘要
肝細胞癌(hepatocellular carcinoma)和病毒性肝炎(viral hepatitis)在台灣都是重要的疾病,因此我們希望對肝臟浸潤淋巴細胞的性質加以探討。在本研究中,我們以酵素分解及梯度離心的方法分離出這些浸潤的淋巴細胞並分析之,以探討其活化及召集的機制。實驗結果顯示由腫瘤組織及非腫瘤組織所分離出的浸潤淋巴細胞大部份為活化的T細胞,並且是以分泌IFNg的Th1和Tc1細胞為主。而在肝臟腫瘤組織中的浸潤淋巴球(tumor-infiltrating lymphocyte,TIL)有較高比例的CD3+ (p<0.05)及CD4+ T細胞(p<0.001),在非腫瘤的肝臟組織所分離出的浸潤淋巴細胞(liver-infiltrating lymphocyte,LIL)則有較高比例的CD56+細胞(p<0.01)。此外我們發現不論是在腫瘤及非腫瘤組織中,CD4+,CD8+,CD56+的浸潤淋巴細胞均會表現趨化激素受器CXCR6。LIL中CD56+細胞表現CXCR6的比例高於TIL中的CD56+細胞(p<0.05)。CXCR6在TIL的CD4+細胞和LIL中的CD56+細胞的表現情況正好和CD4+細胞及CD56+細胞在TIL和LIL中所佔的比例呈正相關,因此TIL和LIL的細胞組成不同可能部份導因於CXCR6在TIL和LIL中各細胞次群的表現量有所不同。我們利用RT-PCR測量CXCR6所對應的趨化激素CXCL16的表現情形,結果發現肝臟腫瘤及非腫瘤組織中均有CXCL16的表現,而在未經過活化的PBMC中則否。我們同時發現肝臟腫瘤及非腫瘤組織中有IL-18的表現。當我們用plate-bound Anti-CD3活化周邊血液單核細胞時,同時加入IL-2及IL-18會使得CXCR6的表現量比單獨加入IL-2時來得低(p<0.05),這顯示在淋巴細胞活化時IL-18的存在與否仍然可能影響到CXCR6的表現量。最後,在利用刀豆素(Concanavalin A, Con A)在C57BL/6小鼠引發肝炎時,利用RT-PCR可以觀察到CXCR6在肝臟及脾臟的表現量均有提升,顯示CXCR6和CXCL16的交互作用不論在人類和小鼠均和肝臟浸潤淋巴細胞的活化與召集密切相關。以上的研究結果將有助於我們進一步了解肝臟浸潤淋巴細胞活化與召集的相關機制。

Abstract
Hepatocellular carcinoma and viral hepatitis both were important diseases in Taiwan. Therefore, we were interested in studying the characteristics of liver-infiltrating lymphocytes. In this study, we used enzymatic digestion and discontinuous centrifugation to isolate these infiltrating lymphocytes and then study the mechanism of the activation and recruitment of liver-infiltrating lymphocytes. Our results indicated that both tumor-infiltrating lymphocytes (TILs) and liver-infiltrating lymphocytes (LILs) from non-tumor part of liver were composed mainly of activated Th1 and Tc1 cells which secreting the cytokine interferon-g. There were significantly more CD3+ (p<0.05) and CD4+ T cells (p<0.001) in TILs than in LILs. In contrast, the LILs contained significantly more CD56+ cells (p<0.01) than in TILs. Besides, we found that a large part of CD4+, CD8+ and CD56+ cells in both TILs and LILs expressed the chemokine receptor CXCR6. The percentage of CXCR6+ cells in CD56+ cells was significantly higher in LILs than in TILs (p<0.05). The expression of CXCR6 in CD4+ cells in TILs and in CD56+ cells in LILs paralleled the percentages of these cells in total infiltrating lymphocytes. This result indicated that the different composition of lymphocyte subpopulation in TILs and LILs could be partially contributed to the differential expression pattern of CXCR6 in each subpopulation. The ligand of CXCR6 was CXCL16. We could detect CXCL16 expression by RT-PCR in both tumor and non-tumor part of liver but not unstimulated PBMCs. We also found IL-18 expression in both tumor and non-tumor part of liver by RT-PCR. When we used plate-bound Anti-CD3 and different cytokines to activate PBMCs, percentage of CXCR6+ cells was significantly lower in PBMCs treated with IL-2 plus IL-18 than in PBMCs treated with IL-2 alone (p<0.05). This suggested that the presence of IL-18 during lymphocyte activation might influence the expression of CXCR6 indirectly. We also showed that the expression of CXCR6 was up-regulated in liver and spleen in Con A induced hepatitis in mice. This indicated that the interaction between CXCR6 and CXCL16 might be involved in the activation and recruitment of liver-infiltrating lymphocytes in both human and mice. Our study would be helpful for further study of the mechanism of activation and recruitment of liver-infiltrating lymphocytes.

目 錄
口試委員會審定書…………………………………………………. i
授權書………………………………………………………………. ii
誌謝…………………………………………………………………. iv
中文摘要…………………………………………………………….vi
英文摘要…………………………………………………………….viii
第一章 緒論………………………………………………………. 1
第一節 研究背景與相關研究……………………………….. 1
一、肝臟浸潤淋巴細胞的組成……………..…………….. 1
二、肝臟浸潤淋巴細胞與病毒性肝炎………….……….. 2
三、肝細胞癌及腫瘤浸潤淋巴細胞…….……………….. 3
四、肝臟浸潤淋巴細胞召集的可能機制……………….. 5
五、趨化激素受器CXCR6及趨化激素CXCL16…….... 8
六、以刀豆素在小鼠建立肝炎的動物模式…………..…. 10
第二節 研究動機與目的…………………………………….. 12
第二章 實驗材料與方法…………………………………………. 14
第一節 實驗材料…………………………………………….. 14
一、 檢體來源及病人特徵………………………………... 14
二、 實驗小鼠……………………………………………... 14
三、 抗體及細胞激素……………………………………... 14
四、 試劑與藥品配方……………………………………... 16
(1)試劑………………………………………………... 16
(2)藥品配方…………………………………………... 20
五、 儀器…………………………………………………... 22
六、 耗材…………………………………………………... 24
第二節 實驗方法…………………………………………….. 25
一、 免疫組織化學染色..…………………………………. 25
二、 分離人類周邊血液單核細胞……………………….. 25
三、 分離人類肝細胞癌內的腫瘤浸潤淋巴細胞與非腫
瘤肝組織中所浸潤的淋巴細胞……………………... 26
四、 表面標記染色………………………..………………. 26
五、 胞內細胞激素染色……………….………………….. 27
六、 反轉錄及聚合酵素連鎖反應……………….……….. 27
(1)RNA之萃取…………………..…..………………. 27
(2)RNA之定量……………………....………………. 28
(3)反轉錄反應………………………..………………. 28
(4)聚合酵素連鎖反應………………..………………. 29
七、 周邊血液單核細胞培養………..……………………. 30
八、 利用刀豆素引發的肝炎及其評估…………...……… 31
九、 統計分析方法………………………………………... 31
第三章 實驗結果……………………………………….………… 32
第一節 肝臟浸潤淋巴細胞之特性………………………..… 32
一、肝臟浸潤淋巴細胞之分布…..……....………………. 32
二、肝臟浸潤淋巴細胞之表面標記分析…....……..……. 33
三、肝臟浸潤淋巴細胞之活化標記分析....……..………. 34
四、肝臟浸潤淋巴細胞之細胞激素分泌情況………..…. 34
第二節 趨化激素受器CXCR6及其相關因子的表現情形... 36
一、 肝臟浸潤淋巴細胞中趨化激素CXCR6的表
現情形………………………………………………... 36
二、 肝細胞癌組織及非腫瘤肝組織內趨化激素CXCL16
及細胞激素IL-18的表現情形………….…………... 37
三、 IL-18與趨化激素受器CXCR6表現量的關係..….... 38
第三節 趨化激素受器CXCR6在小鼠肝炎動物模式中的
表現情形…………………………..…………………. 40
第四章 討論…………………………………………….………… 42
第一節 肝臟浸潤淋巴細胞的基本特質…………………….. 42
第二節 趨化激素受器CXCR6與趨化激素CXCL16在肝
臟浸潤淋巴細胞的活化與召集之中可能扮演的角
色…………………………..…………………………. 46
第三節 IL-18與趨化激素受器CXCR6表現量的關係…..... 50
第四節 趨化激素受器CXCR6在刀豆素引發之肝炎的
表現情形…………………………………………….. 54
第五節 未來展望…………………………………………….. 61
第五章 參考文獻…………………………………………………. 62
第六章 圖表與說明……………………………………

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