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研究生:陳品軒
研究生(外文):Pin-Hsuan Chen
論文名稱:以B型肝炎病毒小鼠模式探討自然殺手T細胞的角色
論文名稱(外文):The role of NKT cells in the mouse model of hepatitis B virus infection
指導教授:許秉寧許秉寧引用關係
口試委員:陳培哲謝世良
口試日期:2015-07-22
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:38
中文關鍵詞:B型肝炎病毒自然殺手T細胞
外文關鍵詞:hepatitis B virusNKT cells
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B型肝炎是個常見的感染並且會引起肝臟急性或慢性的病症。而慢性B型肝炎的患者會有較高的風險變成肝硬化及肝癌而導致死亡,是全球重要的健康課題之一。雖然後天性免疫反應已經被研究得很清楚,並且已知對於控制B型肝炎扮演重要的角色,但是,早期的先天性免疫反應及其參與的細胞仍然不是很清楚。最近,在動物及人類的研究上推測早期自然殺手T細胞對於B型肝炎是有免疫反應的,但是其角色還不是很清楚。在我們的研究中,我們使用了CD1d缺失小鼠,此種老鼠缺失了由CD1d限制的自然殺手T細胞,並經由高壓注射法使小鼠感染B型肝炎病毒來探討自然殺手T細胞對於B型肝炎扮演的角色。結果顯示,在感染B型肝炎病毒後,跟控制組C57BL/6小鼠比起來,CD1d缺失小鼠血清中帶有B型肝炎病毒的比率較高,時間也較長,且無法產生保護性抗體。同時,在感染後期,CD1d缺失小鼠的毒殺性T細胞有exhaustion的現象,此現象導致T細胞毒殺功能受到影響並且無法清除病毒。總結本篇研究,我們推測自然殺手T細胞有助於清除B型肝炎病毒及發展足夠的後天性免疫反應來控制B型肝炎病毒感染。

Hepatitis B virus (HBV) infection is a common infection, which can lead to both acute and chronic liver diseases. HBV infection is a major global health problem and chronic viral infection will lead to chronic hepatitis, cirrhosis and hepatocellular carcinoma. However, although the adaptive immunity is essential for viral clearance and controlling HBV infection, the early innate immunity is hard to demonstrate and the innate immune cells involved in HBV clearance are still poorly defined. Recently, results from animal and human studies suggest early response of natural killer T cells (NKT cells) is involved in HBV infection. However, the role of NKT cells in HBV clearance is still not clear. For further exploration of the role of NKT ells in HBV infection, in this study, we use CD1d-/- mice —which are deficient of CD1d-restricted NKT cells— to study the role of NKT cells against HBV in a mouse animal model with hydrodynamic injection approach. Our results demonstrated that in the CD1d-/- mice, there was a higher HBV-positive rate with prolonged HBV persistence. In addition, the CD1d knockout mice were not able to develop protective antibody compared to wild type C57BL/6 mice. Furthermore, there was increased exhausted phenotype of CD8+ T cells in liver infiltrating lymphocytes at late phase of HBV transfection, which demonstrated the immune dysfunction of T cells and lead to impairment of capacity in HBV viral clearance. Thus, our study suggests that NKT cells are involved in the clearance of HBV and may play a role in the development of sufficient adaptive immune responses to HBV infection.

Table of contents………………………………………………………………………………………………………i
List of figures………………………………………………………………………………………………………iii
Abstract……………………………………………………………………………………………………………………………iv
中文摘要…………………………………………………………………………………………………………………………………vi
Chapter 1 Introduction…………………………………………………………………………………………1
Background…………………………………………………………………………………………………………………………1
1.1 The liver as a lymphoid organ……………………………………………………………1
1.2 Adaptive immune responses toward HBV infection………………2
1.3 Innate immune responses toward HBV infection……………………4
1.4 NKT cells…………………………………………………………………………………………………………………5
1.5 Correlation between viral control and NKT cell
activation………………………………………………………………………………………………………………6
1.6 Rationale…………………………………………………………………………………………………………………8
1.7 Specific aims………………………………………………………………………………………………………9
Chapter 2 Materials and Methods………………………………………………………………10
Chapter 3 Results……………………………………………………………………………………………………13
3.1 Impaired NKT cell development in CD1d-/- mice………………13
3.2 NKT cells are essential for the clearance of HBV
and the ability to produce protective antibody
anti-HBs…………………………………………………………………………………………………………………14
3.3 Immunohistochemistry staining of HBsAg and HBcAg
were higher in the livers of CD1d-/- mice…………………………14
3.4 PD-1 (programmed death-1) is upregulated in liver-
infiltrating CD8+ T cells from CD1d-/- mice with
hepatitis B virus infection………………………………………………………………15
3.5 Liver-infiltrating CD8+ lymphocytes in CD1d-/- mice
displayed the PD-1hiCD127low-exhausted phenotype………15
Chapter 4 Discussion……………………………………………………………………………………………17
4.1 Defects of adenoviral delivery of the HBV genome………17
4.2 NKT cells are involved in the development of
sufficient adaptive immune responses to HBV
infection………………………………………………………………………………………………………………18
4.3 The correlation between NK and NKT cells……………………………19
4.4 The limitations of using CD1d-/- mice……………………………………20
Figures………………………………………………………………………………………………………………………………22
References………………………………………………………………………………………………………………………32


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