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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陶秘華 | |
dc.contributor.author | Chih-Yeh Chen | en |
dc.contributor.author | 陳致曄 | zh_TW |
dc.date.accessioned | 2021-05-16T16:20:10Z | - |
dc.date.available | 2014-09-24 | |
dc.date.available | 2021-05-16T16:20:10Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-06 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6057 | - |
dc.description.abstract | 全世界超過三億五千萬的慢性B型肝炎病毒感染患者至今仍處於產生肝硬化以及肝細胞癌的高風險之下。清除B型肝炎病毒需要有效的B型肝炎專一性胞殺型T細胞的作用,而專一性胞殺型T細胞在急性B型肝炎病毒感染的病人中具備有效抗病毒功能,但是在慢性B型肝炎病毒感染病人中,這些專一性胞殺型T細胞的數目較少,抗病毒功能也較差。臨床報告中,患者體內的B型肝炎病毒劑量被指出與專一性胞殺型T細胞的數量及功能存在負相關趨勢。而免疫反應缺失與病毒劑量的因果關係尚未完全釐清,主要原因在於臨床研究中無法操控病毒感染的劑量,而B型肝炎的自然宿主只有人類、黑猩猩以及樹鼩,缺乏合適的小動物模式用以研究免疫反應缺失的機制。本實驗室近期發展的慢性B型肝炎小鼠模式,透過搭載B型肝炎病毒基因體的腺相關病毒載體(AAV/HBV),使B型肝炎病毒能夠長期在小鼠肝細胞中複製並製造病毒抗原。利用此小鼠模式,我們證明B型肝炎病毒專一性免疫反應有功能缺失的現象,而較高的病毒劑量確實造成較嚴重的功能性缺失,同時造成胞殺型T細胞表現較高量的Programmed death-1(PD-1)等抑制型受器(inhibitory receptors)。PD-1配體(ligand)基因剔除小鼠(PD-L1 KO)於感染AAV/HBV之後,專一性胞殺型T細胞的功能較野生型小鼠的反應為強,而感染後第二週基因剔除小鼠血清中的B型肝炎病毒表面抗原量相較於野生型小鼠顯著下降,顯示PD-1訊息傳導對於B型肝炎專一性胞殺型T細胞免疫功能缺失的重要性。然而當基因剔除小鼠感染高劑量的AAV/HBV時,血清中抗原量在第八週回升至與野生型小鼠相同的程度,顯示PD-1訊息傳導在高劑量B型肝炎病毒感染時僅扮演部分角色。由於此模式中,表現PD-1的胞殺型T細胞無法以專一性五聚體(pentamer)偵測出等量的細胞數,因此以功能性分析與替代性實驗方法證明表現PD-1的胞殺型T細胞具有B型肝炎病毒專一性。本篇研究證明高劑量B型肝炎病毒造成較嚴重的專一性胞殺型T細胞免疫功能缺失,而PD-1訊息傳導在高劑量B型肝炎病毒感染的情況中僅佔有部分貢獻。因此本篇研究提供未來慢性B型肝炎免疫治療的參考依據,利用阻斷PD-1作為慢性B型肝炎免疫治療時,患者體內病毒劑量可能對於治療結果產生影響,需將其列入評估。 | zh_TW |
dc.description.abstract | The viral burdens in chronic hepatitis B patients are correlated with the levels of functional impairment of specific CD8 T cells, which express programmed death 1 (PD-1), and blocking inhibitory signals PD-1 ex vivo augments immunity against hepatitis B virus (HBV). However, due to the limitation of heterogeneity of patients, viral subtypes, and exposure time to viruses, it remains elusive whether the different degrees of T-cell dysfunction are directly induced by the divergence of HBV titers. In addition, the therapeutic effect by blocking PD-1:PD-L1 interaction is yet to be determined under high viral loads. Taking advantage of a mouse model of HBV chronic infection that allows the control of the quantities of monoclonal virus following adeno-associated viral vector delivery of HBV genomic DNA, we demonstrated that the functions of HBV-specific CD8 T cells diminished gradually post infection and T cell dysfunction progressed accompanied with increased viral loads. Consistently, intrahepatic CD8 T cells expressed increasing levels of PD-1 and other inhibitory receptors in a viral load-dependent manner. In PD-L1 KO mice, the functions of specific CD8 T cells were more robust in the early phase of infection, leading to reduced levels of viral antigen. However, activity of anti-HBV T cells sustained only in KO mice with low but not high viral loads, implicating the roles of other immune regulatory factors other than the PD-1:PD-L1 pathway. In addition, the HBV-specificity of PD-1+ CD8 T cells were demonstrated by functional assays and alternative approaches. Collectively, our data indicate that the viral load-induced dysfunction of HBV-specific CD8 T cells is partially regulated by PD-1 pathway, and impeding this pathway alone may not be sufficient to control the persistent infection, particularly in high HBV levels. | en |
dc.description.provenance | Made available in DSpace on 2021-05-16T16:20:10Z (GMT). No. of bitstreams: 1 ntu-102-R00445115-1.pdf: 6508167 bytes, checksum: 9c39b930a52335c4673e2a2df7c918b2 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 1. Introduction 1
1.1 Chronic viral infection 1 1.1.1 T cell exhaustion 2 1.1.2 Inhibitory receptors 3 1.1.3 Effects of viral burdens on T cell exhaustion 4 1.2 Hepatitis B virus (HBV) 4 1.2.1 Genomic structure and genotypes 4 1.2.2 Viral proteins 5 1.2.3 Replication and life cycle 6 1.2.4 HBV infection 7 1.2.5 Immune responses in HBV infection 7 1.2.6 Animal models 8 1.3 Aim of this study 10 2. Materials and Methods 11 2.1 Animals 11 2.2 Adeno-associated viral (AAV) vectors 11 2.3 AAV injection 12 2.4 Immunization 12 2.5 Isolation of splenocytes and intrahepatic lymphocytes 12 2.6 IFN-γ and TNF-α ELISPOT 13 2.7 Serological analysis 13 2.8 Flow cytometric analysis and fluorescence-activating cell sorting (FACS) 14 2.9 In vivo blockade with mAb injection 15 2.10 Preparation of bone marrow-derived dendritic cells (BMDCs) and in vitro adenovirus infection 15 2.11 In vitro T-cell expansion 16 2.12 T cell receptor (TCR) repertoire spectratype analysis 16 2.13 Statistics 17 3. Results 18 3.1 Negative Effects of Viral Loads on The Function of HBV-Specific CD8 T Cells 18 3.2 Intrahepatic T cells from mice with high viral loads expressed higher levels of inhibitory receptors, especially PD-1 19 3.3 The reduction of viral antigens and ameliorated immune responses in the absence of PD-1:PD-L1 interaction 21 3.4 Loss of viral control and HBV-specific responses of CD8 T cells in high viral load mice even in the absence of PD-1:PD-L1 interaction 21 3.5 Blockade of LAG-3 accelerated the reduction of serum HBsAg in PD-L1 KO mice 23 3.6 Identification of H-2Kb-restricted epitopes of HBsAg and HBcAg 23 3.7 Detection of subdominant clones of HBV-specific CD8 T cells which recognize other HBV epitopes during chronic infection 24 3.8 Alternative approaches to demonstrate the HBV-specificity of PD-1+ CD8 T cells 27 4. Discussion 29 4.1 Model advantage 29 4.2 Tolerance 30 4.3 Dose effect 31 4.4 PD-1 expression and other regulatory factors 32 4.5 Blocking PD-1 33 4.6 HBV-specificity of PD-1+ CD8 T cells 35 4.7 Conclusion 36 5. References 38 6. Figures 53 7. Tables 77 | |
dc.language.iso | en | |
dc.title | 利用慢性感染之小鼠模式研究B型肝炎病毒專一性免疫功能缺失之機制 | zh_TW |
dc.title | Studies of the mechanisms underlying the immune dysfunction against HBV in a mouse model of chronic HBV infection | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 朱清良,吳慧琳,楊宏志 | |
dc.subject.keyword | B型肝炎病毒,慢性病毒感染,病毒劑量,免疫功能缺失,PD-1, | zh_TW |
dc.subject.keyword | HBV,chronic viral infection,viral loads,immune dysfunction,PD-1, | en |
dc.relation.page | 80 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-08-06 | |
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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