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研究生:陳亦翔
研究生(外文):YI-Hsiang Chen
論文名稱:合併免疫基因療法與抗血管生成基因療法於原位肝腫瘤之治療
論文名稱(外文):Treatment of orthotopic liver tumors with immunomodulatory and anti-angiogenic gene therapies
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:2004
畢業學年度:92
語文別:中文
論文頁數:91
中文關鍵詞:抗血管生成療法肝細胞腫瘤治療免疫基因療法
外文關鍵詞:Immunotherapyanti-angiogenesis therapyHepatocellular carcinoma
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肝細胞癌為全世界性的疾病,長期位居國人十大死因之一,引起肝細胞癌的原因有許多種,包括病毒性感染、酒精及藥物濫用引起的肝硬化而導致肝細胞癌化,或者是由其他器官腫瘤轉移而來的肝細胞癌。由目前已具有的傳統治療中,如外科手術治療、動脈栓塞或者是化學療法而言,大多只對於較小的肝細胞腫瘤及尚未轉移的腫瘤細胞才具有較好的治療效果;肝臟移植為較好的根除肝細胞腫瘤方法,但是每年捐肝的人數有限,因此找尋新的治療方法並搭配傳統治療就成為近幾年來熱門的研究方向,我們實驗室以免疫基因療法來治療原位性肝腫瘤動物模式,在學長先前的實驗中,以3 x 106 GP7TB細胞建立位在Fischer 344大鼠肝葉上的原位性肝細胞腫瘤,再以3x109 重組腺病毒攜帶GM-CSF基因,以腫瘤內的注射方式治療三天大及七天大的動物腫瘤,實驗結果發現,對於三天大的動物腫瘤,攜帶GM-CSF的重組腺病毒具有很好的療效,但是對於七天大的腫瘤治療效果不好。在我的實驗中,除了大鼠的動物模式之外,尚增加了以3x105 BNL細胞建立位在BALB/c小鼠肝葉上的原位性肝腫瘤。在免疫基因治療中,更進一步合併1x109 攜帶IL-12基因及1 x 109攜帶GM-CSF基因的腺病毒載體,治療七天大及十四天大的原位肝細胞腫瘤,實驗結果發現,對於七天大的原位肝細胞腫瘤,在小鼠或大鼠的動物模式,IL-12合併GM-CSF對腫瘤的清除效果分別達到96.4%及98%,但是對於十四天大的肝細胞腫瘤,治療效果則明顯降低至50%及76%。在以細胞激素刺激的免疫治療中,為了能更進一步有效的治療十四天大的肝細胞腫瘤,我合併抗血管生成基因療法,希望以血管內膜阻生素( endostatin ),抑制腫瘤腫瘤內血管的生成,使得IL-12及GM-CSF刺激的免疫細胞能更進一步有效的清除腫瘤。在實驗中,在重組腺病毒治療的同時,以電擊的方式,分別將100μg及300μg的endostatin質體DNA打入小鼠及大鼠的大腿四頭肌中,並且一星期後再以DNA電擊治療一次,在第28天觀察結果,對於小鼠及大鼠的抑制腫瘤效果分別達到57%及86%。除了腫瘤治療的實驗之外,我另外以特定的抗體去除小鼠內的特定免疫細胞,結果發現,由於GM-CSF對於抑制七天大的小鼠腫瘤模式效果不好,因此去除小鼠的自然殺手細胞、CD4 T細胞及CD8 T細胞,對於GM-CSF抑制腫瘤的結果影響不明顯。以IL-12治療腫瘤,去除自然殺手細胞,會大部分抑制IL-12抑制腫瘤的效果;去除CD4、CD8 T細胞也會些許的抑制IL-12治療腫瘤的效果。以GM-CSF合併IL-12治療腫瘤,抑制小鼠的自然殺手細胞對於治療腫瘤的效果不受影響,推測可能是CD4及CD8細胞在抑制腫瘤細胞扮演重要的角色。
Hepatocellular carcinoma ( HCC ) is a worldwide disease, and is one of the leading cancers in Taiwan. Many reasons can cause HCC, including infection by hepatitis B or C virus, alcohol or drugs abuses, and tumor metastasis to liver. Traditional therapies, such as surgery, or chemotherapy is effective only on small tumors or non-metastatic tumors. Liver transplantation is a better therapy for HCC, but the number of cadaveric donors is limited. Thus combination of new therapies with traditional therapies becomes a topic of intensive research recently. In our laboratory, we have used gene therapy strategies to treat orthotoptic hepatocellular carcinoma. Our previous data demonstrated that, with 3 x 106 of GP7TB cell inoculated in the liver lobe of the Fischer 344 rats, 3 x 109 pfu of adenoviral vector carrying the GM-CSF gene to was effective on the 3-day tumor, but was ineffective on the 7 day-tumor. So, this study investigate whether combination of different cytokine gene therapies may improve the therapeutic effects. Besides the rat model, this study also include a mouse liver tumor model. 3 x 105 BNL cells were inoculated in the liver lobe of BALB/c mice to generate orthotopic liver tumors. I combined adenoviral vector carrying GM-CSF gene with that carrying IL-12 gene to treat the 7-day tumors and the 14-day tumors. The results demonstrate that combined IL-12 and GM-CSF therapy was effective on the 7 day-tumor in both rat and mouse models, but was less effective on the 14-day tumor. To treat 14-day tumor more effectively, I combined immunotherapy with anti-angiogenesis therapy. I investigated whether the anti-angiogenesis factor, endostatin, could improve the efficacy of immunotherapy. The IL-12 and GM-CSF genes were delivered to tumors by adenoviral vectors on day 14 after tumor implantation, and the endostatin gene was transduced into muscle cells by electroporation on days 14 and 21 after tumor implantation. The result showed that combined therapy was indeed more effective than immunotherapy alone. To investigate the roles of different types of immune cells involved in tumor regression, CD4+ T cells, CD8+ T cells or NK cells were depleted in vivo by specific antibodies during the treatment with IL-12 and GM-CSF. It was found that depletion of CD4+ T cells, CD8+ T cells or NK cells reduced the antitumor effects of IL-12, however, depletion of NK cells had no influences on the IL-12 and GM-CSF combined therapy. Thus, CD4+ and CD8+ T cells in the immunotherapy of liver tumors with GM-CSF combined with IL-12, which remains to be determined.
中文摘要……………………………………………………………….7
英文摘要……………………………………………………………….9
前言
肝細胞腫瘤…………………………………………………………..11
免疫反應對腫瘤細胞的監測與耐受性的產生
免疫監測………………………………………………………….12
腫瘤細胞如何躲避免疫反應
1.腫瘤細胞對免疫系統產生抵抗性…………………………….13
2.免疫系統對腫瘤細胞耐受性的產生………………………….15
免疫療法在腫瘤治療上的應用 ………………………………………….18
1. 活化抗原呈現細胞以加強腫瘤抗原的呈現…………………19
2. 活化T細胞免疫反應…………………………………………22
3. 抑制免疫調控因子,打破免疫系統的平衡性………………25
GM-CSF ……………………………………………………….25
IL-12 ………………………………………………………… 26
抗血管生成療法(anti-angiogenesis therapy)……………….27
1. 血管內膜阻生素(endostatin)…………………………….28
2. 血管內膜阻生素(ED)對於內皮細胞的作用機制………….28
3. 輸送方式與腫瘤治療試驗的成果………………………….30
4. 副作用的有無……………………………………………….31
輸送方式的選擇—基因療法
病毒性載體
1. 重組腺病毒載體(Adenoviral vector)……………………32
2. 反轉錄病毒載體(Retroviral Vector)……………………33
3. 腺衛星病毒載體(Adeno-associated Vector)……………34
非病毒性載體
4 DNA直接注射……………………………………………….34
5 微脂粒(liposome)進行基因轉殖…………………………34
6 基因槍(gene gun)基因轉殖………………………………35
實驗目的………………………………………………………………36
材料與方法
細胞的培養………………………………………………………37
高校價病毒的純化與製備………………………………………37
抗體的純化………………………………………………………39
大鼠肝細胞腫瘤動物及腺病毒的治療模式……………………40
延長Endostatin的治療時間對大鼠肝腫瘤的治療結果…….41
小鼠肝細胞腫瘤動物及腺病毒的治療模式……………………43
延長Endostatin的治療時間對小鼠肝腫瘤的治療結果………44
注射重組腺病毒後,小鼠血清內細胞激素的表現量……………45
去除特定的免疫細胞,觀察IL-12及GM-CSF藉由活化何種免疫
細胞來清除腫瘤………………………………………………….46
結果
以重組腺病毒之小鼠血清內GM-CSF及IFN-γ之表現情形…………………………………………………………………47
攜帶細胞激素的腺病毒對七天大的大鼠腫瘤模式的治療果………………………………………………………………48
攜帶細胞激素的腺病毒對十四天大的大鼠腫瘤模式的治療結果………………………………………………………………49
免疫療法合併抗血管生成療法對十四天大的大鼠腫瘤模式的治療結果…………………………………………………………49
攜帶細胞激素的腺病毒對七天大的小鼠腫瘤模式的治療結果………………………………………………………………50
攜帶細胞激素的腺病毒對十四天大的小鼠腫瘤模式的治療結果………………………………………………………………51
免疫療法合併抗血管生成療法對十四天大的小鼠腫瘤模式的治療結果……………………………………………………….51
在小鼠的腫瘤動物模式中,去除特定的免疫細胞對細胞激素活化免疫系統抑制腫瘤的影響………………………………….52
討論…………………………………………………………………54
未來展望………………………………………………………….60
參考文獻………………………………………………………….63
附圖……………………………………………………………....81
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