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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許秉寧 | zh_TW |
| dc.contributor.advisor | Ping-Ning Hsu | en |
| dc.contributor.author | 謝侑靜 | zh_TW |
| dc.contributor.author | Yu-Ching Hsieh | en |
| dc.date.accessioned | 2023-09-22T16:11:52Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-22 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-09 | - |
| dc.identifier.citation | Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatol. 62, 279-291 (2015).
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Lipopolysaccharide-mediated IL-10 transcriptional regulation requires sequential induction of type I IFNs and IL-27 in macrophages. The Journal of Immunology 185, 6599-6607 (2010). | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89806 | - |
| dc.description.abstract | 持續性B型肝炎病毒（HBV) 感染是導致肝硬化或肝癌死亡風險高的一個重要因素。 儘管存在提供高保護率的預防性疫苗，但慢性Ｂ型肝炎帶原攜帶者仍然因 T 細胞反應性受損而無法有效清除體內病毒。 因此，闡明在持續性 HBV 感染的情況下免疫無反應的機制至關重要。 在這篇研究當中，我們在肝臟先從組織核糖核酸定序觀察到白細胞介素 27 （IL-27)在 pAAV/HBV1.2 轉染小鼠的肝臟內有上升的趨勢，也在蛋白質層級中確認肝臟中的IL-27會被B型肝炎病毒誘導並產生。此外，我們透過不同小鼠品系對於病毒清除速率的不同以及核心抗原（Core antigen）缺乏的B型肝炎病毒質體發現了B型肝炎病毒所誘導產生的 IL-27 與病毒持續感染呈現正相關。 而在持續性B型肝炎病毒感染的小鼠肝臟中，出現了一群PD-1+TIM3+的CD8 T細胞群，並且隨著時間增加，這群細胞比例也有所增加，且這群細胞也功能失調（dysfunction)。除此之外，我們發現有一部分由B型肝炎病毒所誘導產生的IL-27源自於巨噬細胞譜系細胞（Macrophage-lineage cells），並以氯膦酸鹽脂質體（Clodronate liposome）將肝臟中的巨噬細胞譜系細胞清除後偵測肝臟中IL-27的量加以證明。最後，我們在IL-27 缺陷小鼠（IL-27-/- mice)體內看到了相較於控制組小鼠（WT)更快的病毒清除率，且那群PD-1+TIM3+ CD8 T細胞群在持續性B型肝炎病毒感染小鼠的肝臟中也顯著降低。此外，在IL-27缺陷小鼠的肝臟中這群CD8 T細胞的功能失調也出現扭轉。 我們的結果顯示著B型肝炎病毒可誘導肝臟微環境之IL-27，且可造成對於肝臟免疫功能的抑制作用，因而增進B型肝炎病毒的持續性感染。這些結果暗示了IL-27在B型肝炎病毒感染期間於肝臟中的抑制作用及其重要性，未來IL-27或許能作為慢性B型肝炎治療的潛在突破點。 | zh_TW |
| dc.description.abstract | Persistent hepatitis B virus (HBV) infection is a prominent factor that causes the high risk of death from cirrhosis or liver cancer. Despite the existence of preventive vaccines that provide a high protection rate, chronic HBV carriers still suffer from failure of viral clearance. Therefore, it is crucial to elucidate the mechanisms of immune tolerance in cases of persistent HBV infection. Here, we observed that interleukin-27 (IL-27) level was strongly induced in the liver of pAAV/HBV1.2-transfected mice by high-throughput sequencing of RNAs (RNA-seq). Moreover, based on core antigen that determines the viral clearance, we found that the elevation of HBV-induced IL-27 was highly correlated with HBV viral persistence, which is characterized by CD8 dysfunction with impaired IFN𝛾 production and enhanced expression of PD-1 and TIM3 in liver infiltrating CD8 T cells, through HBV with core null mutation. To trace the source, we found that a partial of HBV-induced IL-27 is produced by macrophage-lineage cells, and verified through macrophage depletion by clodronate liposomes. Finally, IL-27-/- mice had an enhanced viral clearance, reduced frequency of PD-1+TIM3+ CD8 T cell population, compared to wild-type mice. Besides, the dysfunction of these CD8 T cells was reversed in the liver of IL-27-/- mice. Our findings demonstrated that HBV could induce IL-27 in the liver microenvironment and exert the inhibitory effect on hepatic immune system, which improved the persistence of HBV infection. These results implied the inhibitory role and the importance of IL-27 in the liver during HBV infection and implicated IL-27 as a potential therapeutic target for chronic hepatitis B. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-22T16:11:52Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-22T16:11:52Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 i
致謝 ii 中文摘要 iii Abstract iv Contents v Chapter 1 Introduction 1 1.1 Background 1 1.2 Rationale 10 1.3 Specific aims 11 Chapter 2 Materials and Methods 12 2.1 Materials 12 2.2 Methods 16 Chapter 3 Results 24 3.1 IL-27 production is induced under HBV transfection mouse model 24 3.2 HBV persistence leads to CD8 T cell dysfunction within intrahepatic lymphocytes (IHLs) 25 3.3 IL-27 production is correlated to HBV persistence 26 3.4 Macrophage-lineage cells may be one of the sources that produces IL-27 under HBV infection 26 3.5 CD8 T cell dysfunction was reversed in IL-27 knockout mice and IL-27-/- mice accelerates the clearance of viral titer 28 Chapter 4 Discussion 30 Chapter 5 Summary 33 Figures 34 References 44 | - |
| dc.language.iso | en | - |
| dc.subject | 介白素-27 | zh_TW |
| dc.subject | 巨噬細胞譜系細胞 | zh_TW |
| dc.subject | B型肝炎病毒 | zh_TW |
| dc.subject | Macrophage-lineage cells | en |
| dc.subject | Hepatitis B virus | en |
| dc.subject | IL-27 | en |
| dc.title | B型肝炎病毒可誘導肝臟微環境中IL-27的表現並與病毒的持續感染相關 | zh_TW |
| dc.title | Hepatitis B virus induces IL-27 expression within liver microenvironment and is associated with viral persistence | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.coadvisor | 朱清良 | zh_TW |
| dc.contributor.coadvisor | Ching-Liang Chu | en |
| dc.contributor.oralexamcommittee | 全以祖 | zh_TW |
| dc.contributor.oralexamcommittee | I-Tsu Chyuan | en |
| dc.subject.keyword | 介白素-27,B型肝炎病毒,巨噬細胞譜系細胞, | zh_TW |
| dc.subject.keyword | IL-27,Hepatitis B virus,Macrophage-lineage cells, | en |
| dc.relation.page | 53 | - |
| dc.identifier.doi | 10.6342/NTU202303727 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2023-08-09 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 免疫學研究所 | - |
| dc.date.embargo-lift | 2028-08-08 | - |
| 顯示於系所單位： | 免疫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-111-2.pdf 未授權公開取用 | 3.55 MB | Adobe PDF | 檢視/開啟 |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。