臺灣博碩士論文加值系統

Mouse macrophage inflammatory protein (mMIP) -1α是屬於C-C chemokines的一員，吸引的對象細胞包括巨噬細胞和淋巴球等，進而造成發炎反應；已知MIP-1α的表現能在腫瘤生長處，協同宿主的抗原呈現細胞 (antigen-presenting cells, APCs) 引發具專一性的抗腫瘤細胞毒殺反應；依此特性製作mMIP-1α轉殖的腫瘤細胞疫苗，再結合體外處理的APCs，設計出複合式疫苗，預期對老鼠的腫瘤細胞生長能夠有加強抑制的效果。利用核酸轉殖 (transfection) 的技術，將一個含有mMIP-1α基因的載體送入老鼠的腫瘤細胞，CT26 (BALB/c) 及B16F10 (C57BL/6J) ，並利用酵素聯結免疫吸附分析測試 (ELISA) 篩選出能持續表現mMIP-1α的單株細胞；自老鼠的股骨、脛骨取出骨髓細胞，加入mGM-CSF、mIL-4等細胞激素刺激其中的單核球分化成為樹突細胞 (dendritic cells, DCs)。我們的假設為：先以mMIP-1α轉殖的腫瘤細胞疫苗注射老鼠，使其在注射部位產生發炎反應，隔天再於同一位置注射經體外處理後攜帶有腫瘤抗原的樹突細胞疫苗，預期接受此種複合性疫苗的老鼠更能有效降低或抑制腫瘤細胞的生長，表示mMIP-1α不但能在體內增加週邊DCs浸潤到疫苗注射部位，其所引起的發炎反應也可進一步刺激、活化額外注入的DCs，進一步增強抑制腫瘤生長的免疫反應。
我們的實驗結果顯示，不論是BALB/c或C57BL/6J老鼠，在單獨注射mMIP-1α轉殖的腫瘤細胞疫苗時，對腫瘤細胞的生長都沒有明顯的抑制效果，但是在注射樹突細胞疫苗時，抑制腫瘤生長的效果明顯增強，而在結合兩種疫苗後，發現其效果略勝於單獨注射樹突細胞疫苗；同時我們將兩疫苗注射於同點與不同點的結果相比較，在BALB/c老鼠並沒有看出差異，但在C57BL/6J老鼠的結果發現注射於同一點所產生的抑制能力較強，顯示兩種疫苗之間是有互相加成的效果。結論是，樹突細胞疫苗對腫瘤生長的抑制已經有很好的效果，雖然mMIP-1α轉殖的腫瘤細胞疫苗沒有如預期的結果，但當兩者結合後，仍達到加成的效果；也許未來能以樹突細胞疫苗為主，配合不同條件的mMIP-1α或其他趨化激素轉殖的腫瘤細胞疫苗做研究，期待找出更強的疫苗組合，以達到抑制腫瘤生長的效果。

Mouse macrophage inflammatory protein (mMIP) -1α is a member of the C-C chemokines. It attracts cells including macrophages, lymphocytes and others, and can induce inflammatory responses. It has been reported that the manifestation of MIP-1α can coordinate the antigen presenting cells (APCs) of host to induce specific anti-tumor cytotoxicity in the place where tumor grows.
Our hypothesis is that if we injected mMIP-1α-transfected tumor cell vaccine into mice subcutaneously, we can induce inflammation at the site of injection. If we then inject DC which already carries tumor antigens at the same site, the inflammatory environment might further promote the maturation and activation of these injected, antigen-pulsed DC. We expect that mice treated with this kind of complex vaccines can effectively reduce or suppress the growth of tumor cells. Our results indicate that in both BALB/c and C57BL/6J mice, injection of mMIP-1α-transfected tumor cell vaccine alone did not significantly inhibit tumor growth. Injection of DCs vaccine increased the efficiency of inhibition on tumor growth. When we combined these two vaccines, the efficiency was slightly better than injection with DC vaccine alone. We have found that the efficiency of tumor inhibition was better if the two vaccines were injected at the same site in C57BL/6J mice, but not in BALB/c mice. In conclusion, mMIP-1α-transfected tumor cell vaccine alone did not demonstrate the expected efficiency of tumor inhibition, however, DC vaccine appeared to suppress tumor growth in our systems. After we combined the two kinds of vaccine, the efficiency of tumor inhibition was doubled. These results suggest that we can manipulate DC vaccines and tumor cell vaccines, which are modified with mMIP-1α or other chemokines, in the future to find out a more powerful vaccination strategy for effective inhibition of tumor growth.

目錄
致 謝 I
中文摘要 II
英文摘要 III
目 錄 IV
表圖目錄 V
縮 寫 表 VI
第一章 緒論 1
第二章 文獻回顧 3
1. 樹突細胞 (Dendritic cells, DCs) 3
2. 趨化激素 (Chemokines) 9
3. 腫瘤疫苗 (Tumor vaccine) 13
第三章 實驗儀器與材料 16
1. 實驗細胞株 16
2. 常用儀器 16
3. 常用容液 18
第四章 實驗方法 19
1. 腫瘤細胞的培養 19
2. 建造完成mMIP-1α基因轉殖的細胞株 19
3. 測試mMIP-1α基因轉殖之細胞所產生mMIP-1α的濃度及其生物
活性 22
4. 骨髓衍生之樹突細胞的培養 24
5. 利用流式細胞儀對樹突細胞表面分子的分析 25
6. 輻射劑量測試及細胞存活試驗 26
7. 測試疫苗效果所進行的動物實驗 (Animal model) 27
8. 抑制腫瘤生長機制之研究 29
第五章 實驗結果與分析 32
1. 建造完成mMIP-1α基因轉殖的細胞株 32
2. 測試mMIP-1α基因轉殖之腫瘤細胞所產生mMIP-1α的濃度及其
生物活性 34
3. 測試單獨腫瘤細胞疫苗抗腫瘤生長之效果與可能機轉 35
4. 測試腫瘤細胞疫苗結合樹突細胞疫苗所產生抗腫瘤生長之效果與
可能機轉 38
第六章 討論 42
第七章 參考文獻 48
附圖 VII
表圖目錄
Table 1. 趨化激素之CC家族 60
Table 2. 趨化激素之CXC家族 61
Table 3. 趨化激素的接受體 62
Table 4. 利用流式細胞儀對樹突細胞表面分子的分析所需之抗體組
合 63
Table 5. 結合腫瘤細胞疫苗與樹突細胞疫苗所進行之動物實驗流程及各組注射之內容物 64
Table 6. 進行European releasing assay所需之內容物 65
Table 7. 利用流式細胞儀對實驗動物的脾臟細胞進行分析所需之抗體組合 66
Table 8-1. 利用流式細胞儀對BALB/c實驗老鼠的脾臟細胞進行表面
分子的分析 (表中數字為所佔總細胞數的百分比)
67
Table 8-2. 利用流式細胞儀對C57BL/6J實驗老鼠的脾臟細胞進行表
面分子的分析 (表中數字為所佔總細胞數的百分比)
68
Figure 1. 樹突細胞的生命史 69
Figure 2. 老鼠樹突細胞引導Th1 / Th2細胞活化的模式圖 70
Figure 3. 趨化激素的結構 71
Figure 4. 趨化激素與其接受體作用產生的生物功能 72
Figure 5. 趨化激素刺激樹突細胞、T細胞及B細胞開啟後續免疫反應 73
Figure 6. 趨化激素影響T細胞的極化方向 74
Figure 7. 以電泳實驗回收mMIP-1α的DNA 75
Figure 8. 以電泳實驗回收接合所需的載體pcDNA 3.1 / Zeo 76
Figure 9. 以電泳實驗確認接合成功之plasmid 77
Figure 10. mMIP-1α的濃度測量 78
Figure 11. 利用BALB/c老鼠測試mMIP-1α在體外之生物活性 79
Figure 12. 利用C57BL/6J老鼠測試mMIP-1α在體外之生物活性 80
Figure 13. 利用BrdU incorporation assay測量腫瘤細胞所能承受的輻射劑量 81
Figure 14. 利用MTT assay測量腫瘤細胞所能承受的輻射劑量 82
Figure 15. 測量經過輻射照射後mMIP-1α轉殖之腫瘤細胞於各時間點所分泌mMIP-1α的濃度 83
Figure 16-1. 測試mMIP-1α轉殖的腫瘤細胞疫苗之效果 84
Figure 16-2. 測試mMIP-1α轉殖的腫瘤細胞疫苗之效果 85
Figure 16-3. 測試mMIP-1α轉殖的腫瘤細胞疫苗之效果 86
Figure 17. 測試mMIP-1α轉殖的腫瘤細胞疫苗之效果 87
Figure 18. 骨髓養成的樹突細胞型態 88
Figure 19. 以流式細胞儀分析骨髓養成的DCs其表面分子的表現 89
Figure 20-1. 測試mMIP-1α轉殖的腫瘤細胞疫苗結合DC疫苗所產生的效果 90
Figure 20-2. 測試mMIP-1α轉殖的腫瘤細胞疫苗結合DC疫苗所產生的效果 91
Figure 21. 測試mMIP-1α轉殖的腫瘤細胞疫苗結合DC疫苗所產生的效果 92
Figure 22. 測試BALB/c實驗老鼠之脾臟細胞中，T細胞對CT26細胞的毒殺效果 93

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