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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃麗華 | |
| dc.contributor.author | Pong-Yu Huang | en |
| dc.contributor.author | 黃鵬宇 | zh_TW |
| dc.date.accessioned | 2021-06-17T00:49:29Z | - |
| dc.date.available | 2017-03-02 | |
| dc.date.copyright | 2012-03-02 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-12-01 | |
| dc.identifier.citation | Altomonte, J., Wu, L., Chen, L., Meseck, M., Ebert, O., Garcia-Sastre, A., Fallon, J., and Woo, S.L. (2008). Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. Mol Ther 16, 146-153.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66659 | - |
| dc.description.abstract | 近來有部份的研究報告指出，Sindbis病毒在免疫缺乏的小鼠動物模式中具有溶解以及殺死腫瘤細胞的潛力。然而，其中Sindbis病毒為什麼會特異性地感染腫瘤細胞而不會損害正常細胞的原因仍不明朗。在這篇研究論文中，我們發現影響Sindbis病毒特異性地感染腫瘤細胞的原因可能在於腫瘤細胞干擾素系統的健全與否，而非細胞表面上Sindbis病毒受器的表現多寡。細胞實驗的結果顯示，細胞如果有早期干擾素生成或是晚期干擾素訊息傳遞上的缺陷，會比較容易被Sindbis病毒感染。藉由破壞健全的干擾素系統或是彌補缺損的干擾素反應，細胞可以改變對Sindbis病毒的感受性。我們進一步用動物實驗來證明干擾素反應對Sindbis病毒療法的影響。為更接近臨床情況，我們使用免疫健全的小鼠腫瘤模式。動物實驗的結果顯示，Sindbis病毒的溶瘤效果要在干擾素反應有缺陷的腫瘤中才有效，而且在干擾素訊息傳遞有缺陷的腫瘤中更加顯著。我們也發現在干擾素訊息傳遞有缺陷的腫瘤細胞中，Sindbis病毒量也是相對比較高，並且引起更多的腫瘤細胞產生凋亡。然而，不論干擾素訊息傳遞是否健全或缺損，Sindbis病毒量都很快地下降，約一個星期內病毒就被清除了。這樣的現象很可能是宿主的免疫反應所造成的。同時我們也發現宿主產生抗腫瘤的免疫反應，可以在即使病毒被清除後仍然具有抑制腫瘤生長的效果。如此的免疫反應主要是由CD8 T淋巴球細胞所達成，並且具有免疫記憶的效果。以上的結果顯示，Sindbis病毒療法對於治療干擾素訊息傳遞有缺陷的腫瘤極具有潛力，而且可以引發有效的抗腫瘤免疫反應。 | zh_TW |
| dc.description.abstract | Sindbis virus (SBV) has been shown to possess oncolytic potential in many human xenograft tumor models in immunocompromised mice. However, the mechanism underlying the tumor selectivity of SBV remains undetermined. In this study, we provide evidence that the tumor tropism of SBV infection is not determined by the levels of SBV receptor but by the status of the type I interferon (IFN) response in the tumors. Our results demonstrate that cells with defects in the IFN response in either IFN-β production or IFN signaling were highly susceptible to SBV infection in vitro. The results of oncolysis experiments conducted in immunocompetent animals further confirmed that the success of SBV-mediated oncolysis is greatly dependent on the presence of defects in IFN signaling in tumors. In all cases, viral titers rapidly declined in tumors due to host immune responses in immunocompetent animals. Interestingly, however, tumor-specific immune responses were concomitantly elicited, which might contribute to the sustained antitumor effect observed after the clearance of SBV. These findings indicate that SBV-mediated virotherapy is a promising therapeutic strategy for cancers defective in the IFN response and underscore the importance of bystander antitumor immunity in the efficacy of this virotherapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T00:49:29Z (GMT). No. of bitstreams: 1 ntu-100-D94445007-1.pdf: 2646467 bytes, checksum: 65a1d37792284118fecec0ccf4a1a3b1 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 致謝 i
中文摘要 ii Abstract iii Contents iv Chapter 1 Introduction 1 1.1 Oncolytic viruses 2 1.1.1 Mechanisms of tumor-targeting 2 1.1.2 Clinical progress of oncolytic viruses 5 1.1.3 Induction of antitumor immunity 6 1.2 Sindbis virus 8 1.2.1 Sindbis viral vectors 8 1.2.2 Cellular receptors for Sindbis virus 10 1.2.3 Oncolytic Sindbis virotherapy 12 1.3 Type I interferons 12 1.3.1 Induction of type I interferon 13 1.3.2 Signaling pathway and downstream effects of type I interferon 14 1.3.3 Type I interferon and Sindbis virus 16 1.4 Specific aims of this study 18 1.4.1 Investigation of mechanisms underlying the tumor tropism of SBV 18 1.4.2 Evaluation of Sindbis virotherapy in mouse tumor models 18 Chapter 2 Materials and Methods 20 2.1 Cell culture 21 2.2 Construction of Sindbis viral vectors 22 2.3 Preparation of viruses 23 2.4 Northern blot analysis 24 2.5 Flow cytometric analysis of laminin receptor 24 2.6 IFN-β production assay 25 2.7 IFN signaling assay 26 2.8 Lentivirus-mediated gene knockdown or overexpression 26 2.9 Real-time quantitative RT-PCR 27 2.10 Animal studies 27 2.11 TUNEL assay 29 2.12 Immunohistochemical staining 29 2.13 Cytotoxic T lymphocyte assay 30 2.14 Depletion of CD8+ T cells 30 2.15 Statistical analysis 31 Chapter 3 Results 32 3.1 Construction and characterization of replication-competent Sindbis viral vectors 33 3.2 Measurement of cellular susceptibility to SBV infection 34 3.3 Cellular susceptibility to SBV infection is not determined by the levels of SBV receptor 35 3.4 Cell lines with defects in IFN-β production are susceptible to SBV infection 37 3.5 Cell lines with defects in IFN signaling are susceptible to SBV infection 38 3.6 Modulation of the IFN response alters susceptibility to SBV infection 39 3.7 Establishment and characterization of the IFN signaling-defective ML-14a tumor cell line ARKD 41 3.8 Defects in IFN signaling are important to the success of Sindbis virotherapy in vivo 42 3.9 Sindbis virotherapy induces higher levels of apoptosis in ARKD than in ML-14a tumor tissues 43 3.10 Sindbis viral loads in the ARKD tumors are higher than those in ML-14a tumors 44 3.11 Sindbis virotherapy increases lymphocyte infiltration in tumor tissues 45 3.12 Sindbis virotherapy enhances cytotoxic T lymphocyte response to tumors 46 3.13 Sindbis virotherapy induces immune memory response to tumors 46 3.14 Effector cells of Sindbis virotherapy-mediated antitumor immune response 47 3.15 Sindbis virotherapy induces production of neutralizing antibodies against SBV in tumor-bearing mice 48 Chapter 4 Discussion 49 4.1 The mechanism of the tumor selectivity of SBV is independent of laminin receptor 50 4.2 The status of IFN response plays critical roles in determining cellular susceptibility to SBV infection 51 4.3 SBV load in tumors is quickly declined and is controlled by the host immunity 52 4.4 Roles of host immune responses in Sindbis virotherapy 53 4.5 Conclusions and future directions 54 Chapter 5 Figures and Tables 56 Figure 1 Schematic diagram of the construction of Sindbis viral vector 57 Figure 2 Stability of transgene expression following serial passage in BHK cells 58 Figure 3 Cellular susceptibility to SBV infection 59 Figure 4 Northern blot analysis of the SBV replicative RNA species 60 Figure 5 Microscopic observation of SBV-induced cytopathology of representative cell lines 61 Figure 6 Flow cytometric analysis for surface expression of laminin receptor 62 Figure 7 Analysis of IFN-β mRNA production upon poly(I:C) stimulation 63 Figure 8 Antiviral activities of conditioned medium from the poly(I:C)-treated cells 64 Figure 9 Analysis of ISG56 and ZAP mRNA expression upon IFN-α stimulation 65 Figure 10 Antiviral activities of representative mouse and human cell lines in response to IFN-α stimulation 66 Figure 11 Impairment of IFN response renders cells sensitive to SBV infection 67 Figure 12 Restoration of IFN response renders cells resistant to SBV infection 68 Figure 13 Establishment and characterization of the IFN signaling- defective ML-14a tumor cell line ARKD 69 Figure 14 Sindbis virotherapy in the ML-14a and the ARKD tumor models 70 Figure 15 Sindbis virotherapy in the BNL tumor model 71 Figure 16 Defects in IFN signaling are important to the success of Sindbis virotherapy in vivo 72 Figure 17 TUNEL analysis of apoptotic cells in tumor tissues 73 Figure 18 Sindbis virotherapy induces apoptosis in tumor tissues 74 Figure 19 Sindbis viral loads in the tumors 75 Figure 20 Immunohistochemical analysis for the infiltration of CD8+ and CD4+ T cells in tumor tissues 76 Figure 21 Sindbis virotherapy elicits lymphocyte infiltration in tumor tissues 78 Figure 22 Enhancement of tumor-specific CTL response in the Sindbis virotherapy-treated mice 79 Figure 23 Sindbis virotherapy induces tumor-specific immune memory response in mice 80 Figure 24 The efficiency of CD8+ T cells depletion 81 Figure 25 The roles of CD8+ T cells in the Sindbis virotherapy-mediated antitumor activity 82 Figure 26 Production of neutralizing antibodies in tumor-bearing mice after Sindbis virotherapy 83 Figure 27 A model showing the antitumor effects of Sindbis virotherapy 84 Table 1 Sequences of primers used for construction of Sindbis viral vectors 85 Table 2 Sequences of primers used for quantitative RT-PCR analysis 86 References 87 Appendix 99 | |
| dc.language.iso | en | |
| dc.subject | Sindbis病毒 | zh_TW |
| dc.subject | 溶瘤效應 | zh_TW |
| dc.subject | 病毒療法 | zh_TW |
| dc.subject | 干擾素 | zh_TW |
| dc.subject | 腫瘤 | zh_TW |
| dc.subject | interferon | en |
| dc.subject | oncolysis | en |
| dc.subject | virotherapy | en |
| dc.subject | Sindbis virus | en |
| dc.subject | tumor | en |
| dc.title | 溶瘤式Sindbis病毒攻擊干擾素反應有缺陷的腫瘤並且引發對抗腫瘤的免疫反應 | zh_TW |
| dc.title | Oncolytic Sindbis Virus Targets Tumors Defective in the Interferon Response and Induces Significant Bystander Antitumor Immunity In Vivo | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陶秘華,廖經倫,林宜玲,賈景山,李財坤 | |
| dc.subject.keyword | Sindbis病毒,溶瘤效應,病毒療法,干擾素,腫瘤, | zh_TW |
| dc.subject.keyword | Sindbis virus,oncolysis,virotherapy,interferon,tumor, | en |
| dc.relation.page | 107 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-12-02 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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