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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 朱瑞民 | |
dc.contributor.author | Hsin-Chien Chiang | en |
dc.contributor.author | 江欣蒨 | zh_TW |
dc.date.accessioned | 2021-06-16T10:35:31Z | - |
dc.date.available | 2016-08-01 | |
dc.date.copyright | 2013-08-28 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-14 | |
dc.identifier.citation | References
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60901 | - |
dc.description.abstract | 犬傳染性花柳性腫瘤(CTVT)具有特殊的腫瘤生長模式,包括生長期 (progression phase, P phase) 及自然消退期 (spontaneous regression phase, R phase)。先前研究指出,P期的CTVT細胞會製造高濃度的TGF-β以抑制宿主的抗腫瘤免疫反應;而當腫瘤浸潤淋巴球 (tumor infiltrating lymphocytes, TIL)產生大量的IL-6時,則能抗TGF-β的活性,進而回復宿主的免疫反應,以促使腫瘤消退。雖然目前關於CTVT的腫瘤形成機制已有許多發現,如:CTVT具有抑制樹突狀細胞的功能或是會分泌B細胞毒殺因子等。但我們相信,仍有未知的因子參與在該腫瘤與宿主免疫系統的互動中。在本研究中,我們證實了在CTVT的消退期中,其調控型T細胞的比率較P期時為低,且此變化與R期高量表現的IL-6有關。此外,我們首次利用基因微陣列(GeneChipR Canine Genome 2.0 Arrays Affymetrix array),來比較CTVT P及R期的基因表現變化。其結果顯示,在R期IL-6的升高與TIMD-4, GPNMB 及 PLTP基因的高表現量有正相關性。同時,我們也發現Th17細胞的相關基因會大量表現在R期。綜合前述結果,顯示CTVT的生長可能與調節型T細胞和Th17細胞的數目消長有關。在臨床方面,我們於犬肥大細胞腫瘤及犬淋巴瘤的病犬中檢測Th17細胞及調節型T細胞的比值,發現與健康犬隻相比,腫瘤犬中的Th17細胞皆有顯著性地減少,而調節型T細胞在腫瘤犬中則有顯著性增加,這也證明在犬肥大細胞瘤及犬淋巴瘤中,Th17細胞及調節型T細胞也有不正常的比值。另外,根據基因微陣列分析,我們挑選了幾個在P或R期有大量表現的基因,檢測這些基因是否有可能做為犬腫瘤的生物標記。檢測結果發現CHI3L1可依其表現量來區分惡性犬乳腺腫瘤的級別:在臨床第一期的惡性犬乳腺腫瘤組織中,其CHI3L1的表現量顯著性高於第四、五期;而具有高表現量的CHI3L1病犬,其術後存活時間也顯著性地高於低表現量者。綜合上逑,本研究的結論為:(1) IL-6 在CTVT消退中扮演著重要的角色,因IL-6可回復被TGF-β 所抑制的免疫反應,降低調節型T細胞的產生,且與Th17細胞的增加可能具有相關性。(2) Th17細胞與調節型T細胞異常的比例關係不只在實驗接種的CTVT犬隻中發現,在臨床犬隻腫瘤中也有相同的現象。(3) CHI3L1可做為評估惡性犬乳腺腫瘤預後之因子。 | zh_TW |
dc.description.abstract | Canine transmissible venereal tumor (CTVT) has a unique growth pattern that includes progression (P) and spontaneous regression (R) phases. Previous studies have indicated that a high concentration of TGF-β suppresses host antitumor immunity in the P phase of CTVT. During the R phase, IL-6 derived from tumor infiltrating lymphocytes antagonizes TGF-β activity and restores immunity, leading to CTVT regression. Although many findings such as B cell cytotoxic molecules or inhibition of dendritic cells have been reported to contribute to CTVT development, it is believed that further investigation is needed to disclose the interaction between tumor growth and host immunity. In this study, we demonstrated that IL-6 diminished regulatory T cell (Treg) generation during the R phase. Moreover, using GeneChipR Canine Genome 2.0 Arrays Affymetrix array, we compared the gene expression profiles of P- and R-phase CTVTs for the first time. The results indicated that TIMD-4, GPNMB and PLTP were associated with IL-6 induction during the R phase. We also found that Th17-related genes were up-regulated in the R phase. The discoveries mentioned here imply that there might be an imbalance between Th17 and Treg that results in CTVT progression. Further, the Th17/Treg imbalance in tumors was also validated in clinical cancer patients. We detected the ratios of Th17 and Treg in dogs suffering from mast cell tumor (MCT) and lymphoma (LSA). The results showed a significant decrease of Th17 and a dramatic increase of Treg in dogs with MCT and LSA. This indicated that abnormal ratios of Th17 and Treg are important in canine tumors. In addition, we chose several genes of high expression in the CTVT P and R phases to examine their possible applications as biomarkers in canine tumors. The results demonstrated that a higher expression of CHI3L1 was found in stage I tumors and favored a good prognosis of malignant canine mammary gland tumor (cMGT). Taken together, the results of this study conclude that: (1) IL-6 plays a key role in CTVT regression, as it antagonizes the immunosuppression of TGF-β, reduces Treg generation, and may increase Th17 cells; (2) The imbalance of Th17/Treg exists not only in an experimental CTVT model, but also in clinical canine tumors, which is relevant to patient prognosis. (3) CHI3L1 is a potential biomarker for the prognosis prediction of malignant cMGT. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:35:31Z (GMT). No. of bitstreams: 1 ntu-102-F95629018-1.pdf: 3512627 bytes, checksum: 59f6a36a9d058b998574ee4912783210 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目錄
審查書 i 誌謝 ii 中文摘要 v 英文摘要 vii 目錄 ix 表目錄 xiv 圖目錄 xv Chapter 1 Background 1 1.1 Canine transmissible venereal tumor 1 1.2 Regulatory T cell (Treg) 4 1.3 Th17 cells 8 1.4 CHI3L1 12 1.5 Strategy 14 Chapter 2 Gene expression profiling to identify genes related to spontaneous tumor regression in canine cancer model 15 2.1 Abstract 15 2.2 Introduction 17 2.3 Material and methods 20 2.3.1 Flow cytometric analysis of expression of Treg in healthy dogs and dogs with CTVT P and R phase 20 2.3.2 The most efficient method of culture canine Treg 20 2.3.3 Effect of IL-6 in generation canine Treg 21 2.3.4 Preparations of CTVT supernatants 22 2.3.5 Measurement of extracellular TGFβ1 and IL-6 with ELISA 22 2.3.6 Coculture canine Treg with supernatant from CTVT P and R phase 22 2.3.7 Animals and tumor cell inoculation 23 2.3.8 Tumor sample collection and preparation 24 2.3.9 RNA preparation, microarray hybridization and data analysis 24 2.3.10 Reverse transcription and real-time RT-PCR 26 2.3.11 Network, gene ontology and canonical pathway analysis 26 2.3.12 CD4+ lymphocyte isolation 27 2.3.13 Statistical analysis 28 2.4 Results 29 2.4.1 Investigation of Treg and Th17 in PBMC of dogs in CTVT P and R phase 29 2.4.2 Exploration of Treg change during CTVT growth 29 2.4.3 IL-6 could be an important role to reduce Treg generation in TGF-β-containing medium 29 2.4.4 Analysis tumor regression of CTVT P and R phase 30 2.4.5 Functional and Pathway analysis of the genes with a greater than 2-fold change in the R phase 31 2.4.6 Association of TIMD-4, GPNMB and PLTP with IL-6 production 34 2.4.7 Th17-related genes expressed during the R phase 35 2.5 Discussion 37 2.6 Figures 42 2.7 Tables 59 Chapter 3 Investigation of Th17/Treg in healthy dogs and dogs with cancers 73 3.1 Abstract 73 3.2 Introduction 75 3.3 Material and Methods 78 3.3.1 Animals 78 3.3.2 Flow cytometric analysis of expression of Th17, Treg and Th1 cells 78 3.3.3 Statistical analysis 79 3.4 Results 80 3.4.1 Verification of canine Th17 population in canine PBMC 80 3.4.2 Population of Treg and Th17 in healthy dogs 81 3.4.3 Population and imbalance of Treg and Th17 in dogs with cancers 81 3.5 Discussion 82 3.6 Figures 85 Chapter 4 Chitinase 3-like 1 (CHI3L1) is a potential prognostic marker for canine mammary gland tumors 91 4.1 Abstract 91 4.2 Introduction 92 4.3 Material and Methods 95 4.3.1 Specimens 95 4.3.2 Tissue RNA extraction 95 4.3.3 Reverse transcription and real-time quantitative polymerase chain reaction 95 4.3.4 Statistical analysis 96 4.4 Results 97 4.4.1 Identification of potential biomarkers for canine mammary gland tumors 97 4.4.2 The gene expression level of CHI3L1 could be associated with survival time 97 4.5 Discussions 99 4.6 Figures 103 4.7 Tables 107 Chapter 5 Conclusion 108 References 110 Curriculum Vita 125 表目錄 Table 1 Primer sequences of the most up- (12 genes) and down-regulated (4 genes) genes in spontaneous regression used for real-time RT PCR. 59 Table 2 The biological functions of the genes that were found to be most significantly up-regulated in the CTVT R phase by the 2-fold change method using the Ingenuity Pathway Analysis (IPA) tool. 61 Table 3 The biological functions of genes found to be most significantly down-regulated in the CTVT R phase by the 2-fold change method using the Ingenuity Pathway Analysis (IPA) tool. 64 Table 4 The top five canonical pathways in which their associated genes were most significantly up-regulated during the CTVT R phase. 69 Table 5 The top five canonical pathways in which their associated genes were most significantly down-regulated during the CTVT R phase. 70 Table 6 Primers related to IL-6 expression in the CTVT R phase and used for real-time RT PCR. 71 Table 7 Primers of Th17-related genes used for real-time RT PCR. 72 Table 8 Clinicopathological features of malignant canine mammary gland tumors. 107 圖目錄 Fig 1 Treg population of PBMC in healthy, P phase and R phase of CTVT dogs. 42 Fig 2 in vitro generation of canine Treg from PBMC. 43 Fig 3 Quantification of TGF-β and IL-6 in P and R phase supernatants of CTVT. 45 Fig 4 PBMC coculture with CTVT P and R phase supernatant. 46 Fig 5 The exogenous IL-6 inhibited Treg generation. 48 Fig 6 Analysis pipeline of the gene expression in CTVT P and R phase. 49 Fig 7 IPA analysis of the genes that differently expressed in P- and R-phase tumors. 50 Fig 8 Validation of microarray data from tissues comparing the CTVT P and R phases by real-time RT PCR. 52 Fig 9 IPA analysis of IL-6-associated networks and identification of genes associated with IL-6 network. 56 Fig 10 Expression of Th17-related genes in P phase and R phase of CTVT. 58 Fig 11 Validation of mouse anti-human IL-17A antibody was recognized canine IL-17A by flow cytometry. 85 Fig 12 Identification of canine Th17 population from PBMC of healthy dogs was used by flow cytometry. 86 Fig 13 The population of Treg and Th17 from PBMC of healthy dogs were used by flow cytometry. 87 Fig 14 The change population of Treg and Th17 or the ratio of Th17/Treg from PBMC of dogs with health and cancer. 89 Fig 15 The gene expression of CHI3L1 could be a diagnostic factor to verify stages of canine MGT. 104 Fig 16 Correlation of CHI3L1, MERTK, and APOE expression and overall survival time in cMGT dogs. 106 | |
dc.language.iso | en | |
dc.title | 利用犬隻腫瘤模式探討腫瘤與宿主免疫力之相關性 | zh_TW |
dc.title | Investigation of the correlation between tumor and host immunity in canine tumors | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 林辰栖 | |
dc.contributor.oralexamcommittee | 詹東榮,廖泰慶,廖光文,蔡女滿 | |
dc.subject.keyword | 犬傳染性花柳性腫瘤,犬乳腺腫瘤,犬肥大細胞瘤,犬淋巴瘤,調節型T細胞,Th17細胞, | zh_TW |
dc.subject.keyword | Canine transmissible venereal tumor,canine mammary gland tumor,canine mast cell tumor,canine lymphoma,Treg,Th17, | en |
dc.relation.page | 127 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-14 | |
dc.contributor.author-college | 獸醫專業學院 | zh_TW |
dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
顯示於系所單位: | 獸醫學系 |
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