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研究生:鄭皓薇
研究生(外文):Hao-Wei Cheng
論文名稱:免疫基因療法對原位性肝腫瘤之治療機制及探討
論文名稱(外文):Treatment and Mechanism Study of Immunomodulatory Gene Therapy in Orthotopic Liver Tumor
指導教授:黃麗華黃麗華引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:79
中文關鍵詞:免疫基因療法原位性肝腫瘤
外文關鍵詞:Immunomodulatory gene therapyOrthotopic liver tumor
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肝細胞癌為全世界共通的疾病,也長期位居國人的十大死因之一,在目前的傳統治療中以手術及化學療法為主,但大多只對於較小及尚未轉移的癌細胞有較好的治療效果,因此找尋新的治療方法來搭配傳統治療,就成了最近熱門的研究方向。我們實驗室以免疫基因療法來治療原位性肝腫瘤,先以3 x 105 BNL細胞在BALB/c老鼠肝臟建立原位性肝腫瘤,七天後以攜帶IL-12或合併IL-12及GM-CSF的腺病毒作治療,發現都很有效,且合併治療的效果更好,探究其治療機制發現,在IL-12治療組中, NK為清除腫瘤的主要細胞,而合併治療時,最重要的則是NKT,CD8 T細胞次之;另外抗血管新生的作用在兩個治療組中也都有貢獻。
另外,由於Sindbis virus能在哺乳動物細胞內大量表現外來基因,因此我們希望將此載體系統,應用在腫瘤治療的研究。我們將5 x 104會表現腫瘤抗原mAFP的CT26細胞種在BALB/c老鼠的肝臟,七天後將攜帶CRT-tmAFP、VP22-tmAFP及mAFP的Sindbis virus以肌肉注射的方式,連續三天打入老鼠體內作治療,結果發現CRT-tmAFP及VP22-tmAFP具有治療效果(P < 0.05),mAFP則和控制組無差別。未來希望能進一步改進,讓治療效果更好。
Hepatocellular carcinoma (HCC) is a worldwide disease, and is one of the leading cancers in Taiwan. Traditional therapies, such as surgery or chemotherapy, were effective only on small tumors or non-metastatic tumors. Thus, searching for new therapeutic strategies has become a topic of intensive research recently. In our laboratory, we have used gene therapy strategies to treat orthotopic hepatocellular carcinoma. Mouse hepatoma cells BNL were inoculated in the liver lobe of BALB/c mice to generate orthotopic liver tumor. Then, adenoviruses carrying IL-12 gene or combination of IL-12 and GM-CSF genes were used to treat tumors seven days after tumor cells inoculation. The results showed that both treatments significantly inhibited tumor growth, but the therapeutic effects of combination therapy were better than IL-12 monotherapy. The most important effector cells involved in the IL-12 treatment were NK cells, whereas those in the combination therapy were NKT cells and CD8 T cells.
In the second part, we employed Sindbis viral vector, which could express high level of heterologous genes in mammalian cells, to direct tomor-associated antigen (TAA) expression and performed TAA-based immunotherapy. CT26 cells expressing tumor antigen mAFP were inoculated in the liver lobe of BALB/c mice to generate liver tumor. Seven days after tumor inoculation, mice were immunized intramuscularly with Sindbis virus expressing CRT-tmAFP, VP22-tmAFP or mAFP for three constituitive days. The results indicated that fusion of CRT or VP22 with mAFP induced significant immunity against mAFP-expressing tumors. Further studies are still needed to improve the strategy in the future.
中文摘要……………………………………………………………………... I
英文摘要……………………………………………………………………... II
目錄……...………………………………………………………………….... IV
緒論…………………………………………………………………………... 1
一、肝細胞腫瘤…………………………………………………………... 1
二、基因療法於腫瘤治療上的應用……………………………………... 1
(一)抗血管新生療法….………………………………………………... 1
(二)改善基因表現….…………………………………………………... 2
(三)自殺基因療法.……………………………………………………... 3
(四)使用oncolytic virus ………………………………………...……... 4
(五)免疫療法…………………………………………………….……... 5
三、免疫療法於肝腫瘤治療的應用……………………………………... 6
四、Sindbis virus背景介紹及於疫苗上的應用…………………………... 7
第一部分 探討免疫基因療法於原位肝腫瘤之治療機制………………... 11
研究目的…………………………………………………………………... 12
材料與方法………………………………………………………………... 13
一、細胞株培養…………………………………………………………… 13
二、小鼠肝細胞腫瘤及治療模式………………………………………… 13
三、注射重組腺病毒後血清內IFNγ的表現量……………………….…. 14
四、以抗體中和IFNγ觀察其在治療上扮演的角色………………………14
五、以免疫組織染色分析腫瘤組織的CD31分子表現量…………………14
六、治療結束後再次打入腫瘤細胞的challenge實驗…………………… 15
七、in vitro NK killing assay……………………………………………… 15
八、in vitro killing assay……………………………………………………16
九、統計分析………………………………………………………………17
結果…………………………………………………………………………18
一、以重組腺病毒治療後老鼠血清內的IFNγ表現情形………………18
二、使用中和性抗體,觀察IFNγ是否在IL-12及合併治療的療效上扮演重要角色………………………………………18
三、in vitro NK killing assay,觀察自然殺手細胞活化後毒殺YAC-1 細胞的能力…………………………………19
四、治療結束後再次植腫瘤於肝臟或皮下,觀察先前的治療是否誘發記憶型T細胞…………………………………19
五、以流式細胞儀分析TIL裡各免疫細胞的數量及NKT細胞的組成…………………………………20
六、在不同時間點分離MNL進行in vitro killing assay…………………………………21
七、以攜帶細胞激素的腺病毒作治療具有抗血管新生的功能……………………21
討論……………………………………………………………………23
第二部份 使用腫瘤相關抗原來引發抗腫瘤免疫反應……………27
研究目的………………………………………………………………28
材料與方法……………………………………………………………29
一、Sindbis DNA載體之改造…………………………………………29
二、細胞株培養………………………………………………………30
三、以磷酸鈣沉澱法轉染DNA至293T細胞…………………………30
四、以西方墨點法分析重組病毒感染細胞後的表現………………31
五、構築及生產會表現mAFP的lentivirus…………………………31
六、確定lentivirus的mAFP表現……………………………………32
七、超級感染…………………………………………………………32
八、確定CT26細胞株mAFP表現………………………………………32
九、小鼠肝細胞腫瘤及治療模式……………………………………33
十、以免疫組織染色分析腫瘤組織的CD31分子表現量……………33
十一、統計分析………………………………………………………34
結果……………………………………………………………………35
一、確定Sindbis疫苗的表現…………………………………………35
以西方墨點法分析舊載體的表現………………………………… 35
以西方墨點法分析接有capsid之新載體的表現………………… 36
二、Stable clone的建立及動物實驗的進行………………………37
以pHR’-CSW-IRES-Neo建立stable clone…………………… 37
以S2系統建立stable clone……………………………………… 37
以CT26(4)/mAFP為腫瘤模式進行動物實驗……………………38
分析腫瘤內的血管數目………………………………………………38
構築會表現mAFP的pSIN-MCS載體.………………………….….…39
對CT26(5)/mAFP細胞超級感染後,以西方墨點法分析mAFP表現…39
討論……………………………………………………………………41
參考文獻………………………………………………………………45
附圖…………………………………………………………………55
附錄………………………………………………………………72
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