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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張金堅(King-Jen Chang),許博欽(Bor-Ching Sheu) | |
| dc.contributor.author | Chao-Hsu Li | en |
| dc.contributor.author | 李朝樹 | zh_TW |
| dc.date.accessioned | 2021-05-20T21:38:36Z | - |
| dc.date.available | 2010-09-09 | |
| dc.date.available | 2021-05-20T21:38:36Z | - |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-14 | |
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Coyle, Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation, J Immunol 166 (2001), pp. 1-5. [59] C.T. Viehl, T.T. Moore, U.K. Liyanage, D.M. Frey, J.P. Ehlers, T.J. Eberlein, et al., Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice, Ann Surg Oncol 13 (2006), pp. 1252-1258. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10550 | - |
| dc.description.abstract | 背景與目的
腫瘤細胞的生長需對抗來自宿主免疫系統的清除作用，在腫瘤組織微環境中有大量的浸潤淋巴球聚集（tumor infiltrating lymphocytes，TILs）。其中有一群 T 細胞具有調節免疫作用，具有 CD4+CD25+ 表現特徵，稱為調節性 T 細胞。調節性 T 細胞於細胞內高度表現 FOXP3 轉錄分子，其負向調節作用需靠細胞與細胞接觸的機制。許多的研究指出腫瘤細胞的免疫逃脫機制有調節性 T 細胞參與。T 細胞經過與抗原表現細胞接觸後受到刺激，naive cell 會轉化成記憶 T 細胞，之後若經一定刺激可以再度被活化。記憶 T 細胞（memory T lymphocyte）以返回次級淋巴器官的能力與 effector 的功能區分為兩種類型：central memory cell（TCM）及 effector memory cell（TEM）。依據之前本實驗室對乳癌病患腫瘤浸潤淋巴球的測定，發現 TIL 中的 CD8+ T 細胞的比例會增加，而 CD4+ T 細胞的比例會減少。而增加的 CD8+ T 細胞顯著與乳癌疾病期別進展有相關。CD8+ T 細胞具有毒殺腫瘤細胞能力，但於腫瘤微環境中由於免疫功能被抑制，其毒殺腫瘤細胞能力亦被抑制。我們欲了解乳癌病患 TILs 中調節性 T 細胞與 CD8+ T 細胞其免疫標記表現與細胞毒殺能力的關係，尤其是記憶細胞是否能經刺激後再具免疫功能，希望能對未來發展對腫瘤的免疫治療有所幫助。 材料與方法 實驗標本的收集：臨床診斷第一至第三期乳癌的病患，依疾病狀況接受手術治療。病患乳癌腫瘤組織（註記為 TIL）將會被收集成實驗組。同時收集病患的血液（註記為 PBL）為對照組。依據病理報告的結果，記錄每個病例的臨床病理特徵。在分離純化浸潤淋巴細胞與分離出周邊血液中的單核細胞後對細胞表面抗原與細胞內作用分子作測定，運用流式細胞儀分析。探討 TIL 中CD4+CD25+ 調節性 T 細胞及其上 FOXP3、GITR、CD103 和 CD152（CTLA-4） 的表現，及探討調節性 T 細胞分泌 cytokine 的表現，最後探討調節性 T 細胞對 CD8+ T 細胞毒殺能力之影響。也分析調節性 T 細胞與 CD8+記憶 T 細胞及 effector cell 表現之相關。然後我們將檢測 CD4+CD25+ 調節性 T 細胞分泌 Th1 cytokines（IFN-γ、IL-12 和 TNF-α）與 Th2 cytokines（IL-4 和IL-10）的狀態，也對細胞內毒殺顆粒（包括 granzyme B 及 perforin）的表現作分析。 結果 共有30位病患列入分析，性別均為女性，平均年齡為56.8歲（28歲至89歲）。CD4+CD25+ 調節性 T 細胞在腫瘤中的比例與血液相比為增加（11.6 | zh_TW |
| dc.description.abstract | Background:
To determine the functional attributes of CD4+CD25+regulatory T cells (Tregs) in cancer microenvironment . Material and Methods: Triple-color flow cytometry was utilized to study the phenotype expression of CD4+CD25+Tregs and CD8+T-cell in the peripheral blood lymphocytes (PBLs) and tumor infiltrating lymphocytes (TILs) of 30 stage I to III breast cancer. Results: The prevalence of CD4+CD25+T cells was significantly higher in the TILs than PBLs. The expression of FOXP3, CD103 and GITR on CD4+CD25+Tregs was lower in PBLs than TILs. Most tumor-infiltrating CD8+T cells were CD28-CD45RA-CD45RO+CCR7-, suggesting good terminal differentiation. Most of them had an activated role with CD69+CD103+CD152+. Functionally, both granzyme B and perforin were scarcely expressed in peripheral Tregs but were highly expressed in Treg cells in the tumor micro-environment. On the contrary, CD8+cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and were significantly higher than those in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8+cytotoxic T cells. Conclusions: Tregs in the tumor microenvironment may abrogate CD8+T cell cytotoxicity in a granzyme B-and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for Treg-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of Tregs in TILs may mediate T-cell immune repression within cancer milieu. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T21:38:36Z (GMT). No. of bitstreams: 1 ntu-99-P96421004-1.pdf: 1096238 bytes, checksum: 4e0b8cf3c39f456df0ea3eea4d94e91e (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii Abstract vi 第一章 緒論 1 第一節 研究背景 1 腫瘤微環境與免疫系統 1 調節性T細胞 1 記憶T細胞 2 第二節 腫瘤浸潤細胞與癌症相關性之文獻回顧 2 第三節 研究目的 3 第四節 研究的假說 4 第二章 研究方法與材料 5 第一節 研究材料 5 實驗標本的收集 5 病歷基本資料登錄 5 第二節 研究方法 5 分離純化浸潤淋巴細胞 5 細胞表面免疫標記測定 6 細胞內細胞激素的染色 7 流式細胞儀分析 7 細胞收集 7 細胞培養 8 第三節 分析方法 9 表現比例的定義 9 分析軟體與統計分析 9 第三章 結果 10 第一節 比較Treg與CD8+ T細胞 10 個案基本資料 10 乳癌病患的腫瘤內浸潤淋巴球含有較高比例的 CD4+CD25+調節T細胞 10 乳癌病患的腫瘤內浸潤淋巴細胞與週邊血液淋巴細胞細胞CD4+CD25+ 調節性T細胞的組成不同 10 乳癌病患腫瘤內的CD4+CD25+調節性T細胞表現較高的FOXP3、GITR與CD103 10 乳癌腫瘤內各種記憶T8細胞的表現 11 第二節 分析毒殺細胞分子與誘發實驗 11 乳癌病患腫瘤內CD4+CD25+調節性T細胞表現較多毒殺顆粒 11 乳癌腫瘤內CD8+ T細胞功能被抑制 11 乳癌腫瘤內浸潤淋巴球的Th1細胞激素分泌可被誘發 11 乳癌腫瘤內CD8+ T細胞被抑制的功能是可回復的 12 第四章 討論 13 第五章 展望 17 第六章 論文英文簡述 18 Introduction 18 Materials And Methods 19 Patient Recruitment 19 Collection of Tumor Tissue and Peripheral Blood 19 Immunophenotyping Analysis by Flow Cytometry 19 Cell Culture 20 Definition of expression ratio (ER) 21 Statistical Analysis 21 Results 21 Compositional differences of CD4+CD25+ Treg cells in PBLs and TILs in breast cancer patients 21 Significant functional compromise of CD8+TILs derived from breast cancer 22 Treg-mediated immunosuppression of CD8+TILs is reversible 23 Enhanced Th1 Cytokine Production can be achieved in TILs from breast cancer 24 Up-regulated expression of Perforin and Granzyme B in TILs 24 Discussion 24 表一 35 圖一 36 圖二 37 圖三 38 圖四 40 圖五 41 圖六 42 | |
| dc.language.iso | zh-TW | |
| dc.title | 乳癌腫瘤浸潤淋巴細胞分析:比較調節性T細胞、CD8+T細胞與相關免疫標記的表現 | zh_TW |
| dc.title | Expression and Cell Markers of Regulatory T Cells and CD8+ T Cells in Tumor-Infiltrating Lymphocytes of Human Breast Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.advisor-orcid | ,許博欽(bcsheu@ntu.edu.tw) | |
| dc.contributor.oralexamcommittee | 楊偉勛(Wei-Shiung Yang) | |
| dc.subject.keyword | 乳癌,調節性T細胞,CD8+ T細胞,腫瘤浸潤淋巴球,記憶T細胞, | zh_TW |
| dc.subject.keyword | Breast cancer,regulatory T cells,CD8+ T cells,tumor-infiltrating lymphocytes,memory T cells, | en |
| dc.relation.page | 42 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2010-08-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
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| ntu-99-1.pdf | 1.07 MB | Adobe PDF | 檢視/開啟 |
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