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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陶秘華(Mi-Hua Tao) | |
| dc.contributor.author | Li-Yi Chen | en |
| dc.contributor.author | 陳俐儀 | zh_TW |
| dc.date.accessioned | 2021-06-13T07:59:07Z | - |
| dc.date.available | 2010-08-02 | |
| dc.date.copyright | 2005-08-02 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-22 | |
| dc.identifier.citation | 1. Lee, W. M. 1997. Hepatitis B virus infection. N Engl J Med 337:1733.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/36388 | - |
| dc.description.abstract | 台灣成年人中有高達20%的人口為B型肝炎帶原者，這些慢性B型肝炎患者為肝硬化及肝癌的高危險群，且每年造成全球死亡人次超過一百萬人。因此，發展有效的慢性B型肝炎療法，仍然是相當重要。許多研究證據支持，慢性B型肝炎患者體內若是具有活化狀態的B型肝炎病毒特異性T細胞，便能抑制B型肝炎病毒複製。因此，利用細胞繼代免疫療法將大量活化的B型肝炎病毒特異性T細胞重新輸回慢性B型肝炎患者體內，預期將能治療慢性B型肝炎。現今進行細胞繼代免疫療法時，多採用棘狀細胞外加月生肽來刺激T細胞增生，但是製造棘狀細胞昂貴且複雜。因此，我們以人造抗原呈獻細胞（aAPC）作為一種新的抗原呈獻細胞來源，來增生細胞繼代免疫療法時所需的T細胞。
有效的T細胞活化需要接受不同的刺激。透過月生肽-主要組織相容性複合物（peptide：MHC）與T細胞受器相連結，APC傳遞第一個訊息給遭遇抗原的T細胞。相同的APC同時也傳遞第二道訊息，即共刺激訊息給T細胞。 在此研究中，我們試著發展aAPC的系統來增生HBV特異性毒殺T細胞。設計以纖維母細胞為基礎的aAPC，在其上表現單鏈HBs28-39-β2微球蛋白-H2Ld（訊息一），膜結合態的單鏈抗小鼠4-1BB變異片段（訊息二）以及T細胞生長因子，介白素-2或介白素-15。透過流式細胞儀偵測aAPC細胞表面HBs-H2Ld和anti-4-1BB的表現量。我們也證明這些aAPCs能夠分泌具有功能的介白素-2或是介白素-15。在一次的實驗中，我們以人造抗原呈獻細胞刺激出少量（約3%）的小鼠HBs特異性CD8 T細胞。然而，以細胞毒殺試驗評估HBs-H2Ld的生物功能時，表現HBs-H2Ld的細胞卻無法被HBs特異性T細胞毒殺。因此，我們需以更多的實驗來驗證aAPC是否具有功能。 本文第二部分為分離人類周邊血液單核細胞並確定經冷凍保存的單核細胞仍然保有增生能力。此外，我們以人類單核球分化成具有成熟棘狀細胞型態及表現型的CD83+棘狀細胞。 | zh_TW |
| dc.description.abstract | Up to 20% of adults in Taiwan are chronic carriers of hepatitis B. These chronic carriers have a high risk of developing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Worldwide deaths from HBV-associated liver cancer exceed one million per year. Thus, development of an effective treatment for chronic hepatitis B (CHB) patients is of medical importance. Many studies suggest that viral replication in chronic hepatitis B patients could be inhibited by activated HBV-specific cytotoxic T cells. Therefore, adoptive transfer activated HBV specific CTLs into CHB patients represents a promising method to treat CHB. For adoptive immunotherapy, one commonly used approach for induction and expansion of antigen-specific CTLs has been based on the use of antigen-loaded dendritic cells as antigen presenting cells. However, generation and maintenance of DCs is costly and cumbersome. An alternative source of APC, artificial antigen-presenting cell (aAPC), is therefore designed to stimulate the expansion and acquisition of optimal therapeutic features of T cells.
Efficient T-cell activation requires stimulation of a combination of signals. Antigen encountered T cells receive the first signal through engagement of the T-cell receptor with peptide：MHC (major histocompatibility complex) complexes on APCs. At the same time, a second signal, the co-stimulatory signal, is delivered by the same APC. In this study, we aimed to develop aAPC systems to expand HBV-specific CTLs. The fibroblast-based aAPCs were engineered to express a single chain HBs28-39-β2 microglobulin-H2Ld complex (signal 1), a membrane anchored anti-4-1BB single- chain Fv fragments (scFv) (signal 2) as well as T-cell growth and stimulating factor, IL-2 or IL-15. Expression of HBs-H2Ld and anti-4-1BB scFv protein was detected by FACS analysis of aAPCs. We also demonstrated that these aAPCs release a significant amount of biologically active IL-2 and IL-15. In one experiment, we found that these aAPCs could induce a small percentage (~ 3%) HBs-specific CTLs in vitro as detected by MHC pentamer staining. However, in other experiments HBs-β2m- H2Ld-expressing target cells were not sensitized for lysis by HBs-specific CTLs in a 51Cr-release assay. Further experiments are required to resolve this discrepancy. In the second part of the study, we isolated human peripheral mononuclear cells, and proved that their proliferative activity was preserved after cryopreservation. We also set up techniques to culture plastic-adherent blood monocytes and stimulated their differentiation into CD83+ cells with immunophenotypic and morphologic characteristic of mature dendritic cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T07:59:07Z (GMT). No. of bitstreams: 1 ntu-94-R92424011-1.pdf: 1804148 bytes, checksum: 717df148895f981b55c0767b5173e7a5 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 目錄 I
中文摘要 V Abstract VI 圖次 VIII 縮寫表 X 第一章、序論 1 壹、B型肝炎病毒簡介 (Hepatitis B virus，HBV) 1 貳、B型肝炎病毒的致病機轉 2 參、細胞繼代免疫療法Cellular Adoptive immunotherapy 4 肆、人造抗原呈獻細胞 （Artificial APC，aAPC） 6 伍、單鏈主要組織相容性複合體（scMHC）--- 訊息一 8 陸、單鏈抗小鼠4-1BB變異片段 (anti-4-1BB scFv) --- 訊息二 8 柒、細胞激素 --- 訊息三 10 捌、製造人類棘狀細胞 10 玖、實驗目的 10 第二章、材料與方法 12 第一節、質體的構築 12 壹、質體的製備 (Nucleobond AX，Macherey-Nagel，Cat. No. 740545) 12 貳、聚合酶連鎖反應 (Polymerase Chain Reaction，PCR) 12 參、1 % 洋菜膠電泳 (1% agarose gel electrophoresis) 13 肆、DNA 片段分離 (QIAquick Gel Extraction kit，QIAGEN，Cat. No. 28704) 13 伍、Zero Blunt TOPO PCR Cloning (Invitrogen,Cat. No. K2800-20) …………………………………………………………….14 陸、限制酵素切割反應 (Restriction enzyme digestion) 14 柒、DNA接合反應 (T4 DNA ligase，Invitrogen , Cat No. 15224-017). 14 捌、細菌電擊轉殖法(Electro transformation) 14 第二節、細胞株與細胞培養 15 第三節、重組反轉錄病毒的構築 (Recombinant retrovirus construction) 15 壹、反轉錄病毒載體與包裝細胞的構築 (Clontech，Cat. No. 6102-1). 15 貳、反轉錄病毒包裝細胞 (PT67 packaging cell line)的轉染 (Clontech，Cat. No. K1060-D) 16 參、標的細胞 (Target cell) 的感染與篩選 17 第四節、蛋白質在真核細胞中的表現 17 壹、真核細胞的轉染 (Transfection) 17 貳、西方墨漬法(western blot) 18 參、酵素連結免疫分析法 (Enzyme Linked ImmunoSorbent Assay，ELISA) 19 肆、細胞表面分子的免疫螢光染色分析 20 伍、以HT-2細胞測定細胞激素之生物活性 21 陸、毒殺性T淋巴球試驗 (Cytotoxic T lymphocyte assay) 21 第五節、動物實驗 23 壹、實驗動物來源 23 貳、使用的疫苗 23 參、小鼠的免疫注射方式 24 肆、小鼠的活體內電擊 24 伍、脾臟細胞的置備 24 陸、淋巴結細胞的置備 25 柒、培養小鼠棘狀細胞 25 第三章、實驗結果 27 第一部、 誘發及增生抗原特異性CD8 T 細胞 27 第一節、 人造抗原呈獻細胞的置備及其功能的分析 27 壹、構築同時表現單鏈抗小鼠4-1BB變異片段及細胞激素（介白素-2或介白素-15）的反轉錄病毒載體 27 貳、重組反轉錄病毒感染3T3纖維母細胞 31 參、挑選重組反轉錄病毒感染後合適的單一細胞克隆 32 肆、構築單鏈HBs-β2微球蛋白(β2-microglobulin,β2m)- H2Ld及單鏈β2 m– H2Ld的反轉錄病毒載體 35 伍、重組反轉錄病毒感染3T3及表現H2Ld的單一細胞 37 陸、分析篩選後之永久表現的人造抗原呈獻細胞 39 柒、以細胞毒殺反應進行單鏈HBs-β2m-H2Ld功能測試 40 第二節、 以小鼠棘狀細胞及人造抗原呈獻細胞誘發及增生HBs 抗原特異性CD8 T細胞 40 壹、培養小鼠棘狀細胞，分析表面immunophenotype 41 貳、DNA疫苗引發HBV S蛋白的細胞性及體液性免疫反應 41 參、不同免疫次數對細胞毒殺反應的影響 42 肆、體外刺激HBs抗原特異性CD8 T細胞 42 第二部、培養人類周邊血液單核細胞及棘狀細胞 44 第一節、製備人類周邊血液單核細胞群 45 第二節、 測量淋巴細胞活性---分裂素（Mitogen）誘發周邊血液單核細胞增生 45 第三節、 由單核球(monocyte)製造人類棘狀細胞 46 第四節、以細胞激素誘使單核球分化 47 壹、 棘狀細胞型態變化 47 貳、 未成熟與成熟棘狀細胞表面表現型（phenotype）的差異…… 47 參、 異體 mix lymphocyte reaction（allo-MLR）分析成熟棘狀細胞刺激T細胞能力 48 第四章、討論 49 檢視單鏈HBs-H2Ld不具有功能的原因 50 檢視介白素-2和介白素-15產量的差異 52 成熟棘狀細胞標記---CD83分子的特性 54 第五章、參考文獻 56 圖片 66 表一、人造抗原呈獻細胞列表及基因片段結構圖 106 附錄一 107 附錄二 108 附錄三 115 附錄四 117 | |
| dc.language.iso | zh-TW | |
| dc.subject | 毒殺性T細胞 | zh_TW |
| dc.subject | B型肝炎 | zh_TW |
| dc.subject | 人造抗原呈獻細胞 | zh_TW |
| dc.subject | 棘狀細胞 | zh_TW |
| dc.subject | dendritic cell | en |
| dc.subject | artificial antigen presenting cell | en |
| dc.subject | CD8 T cell | en |
| dc.subject | hepatitis B virus | en |
| dc.title | 構築B型肝炎病毒之人造抗原呈獻細胞 | zh_TW |
| dc.title | Construction of Artificial Antigen Presenting Cell for Hepatitis B Virus Research | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 胡忠怡(Chung-Yi Hu),張淑媛(Su-Yuan Chang),陳健弘(Chien-Hung Chen) | |
| dc.subject.keyword | 人造抗原呈獻細胞,B型肝炎,毒殺性T細胞,棘狀細胞, | zh_TW |
| dc.subject.keyword | artificial antigen presenting cell,hepatitis B virus,CD8 T cell,dendritic cell, | en |
| dc.relation.page | 118 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-22 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫事技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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