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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許秉寧(Ping-Ning Hsu) | |
| dc.contributor.author | Hua-Yi Lee | en |
| dc.contributor.author | 李華翊 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:32:46Z | - |
| dc.date.available | 2021-08-31 | |
| dc.date.available | 2022-11-24T03:32:46Z | - |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-10 | |
| dc.identifier.citation | Alvarez, E., Berg, P.A., Bianchi, F.B., Bianchi, L., Burroughs, A.K., Cancado, E.L., Chapman, R.W., Cooksley, W.G.E., Czaja, A.J., Desmet, V.J., et al. (1999). International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31, 929-938. Arshad, M.I., Piquet-Pellorce, C., L'Helgoualc'h, A., Rauch, M., Patrat-Delon, S., Ezan, F., Lucas-Clerc, C., Nabti, S., Lehuen, A., Cubero, F.J., et al. (2012). TRAIL But Not FasL and TNF alpha, Regulates IL-33 Expression in Murine Hepatocytes During Acute Hepatitis. Hepatology 56, 2353-2362. Bach, E.A., Aguet, M., and Schreiber, R.D. (1997). The IFN gamma receptor: A paradigm for cytokine receptor signaling. Annu Rev Immunol 15, 563- . Bartsch L.M., Damasio MPS., Subudhi S., Drescher H.K.. Tissue-Resident Memory T Cells in the Liver-Unique Characteristics of Local Specialists. (2020). Cells 9(11):2457. Bazan, J.F. (1990). 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81143 | - |
| dc.description.abstract | "組織駐留記憶性T細胞 (Tissue Resident Memory, TRM) 是一群近年才被分類出來的細胞次群，根據其容易停留於特定組織或器官中而非跟著血液流動循環的能力而得名。與循環血中的中央記憶性 (Central memory, TCM) 與效應記憶性 (Effector memory, TEM) T細胞在表徵上、轉錄體表現上甚至於功能上都非常不同。先前於本實驗室的研究中指出，在尚未敏化的小鼠肝臟中有一群高度表現無唾液酸神經節苷脂 (Asialo-GM1, ASGM1)的CD8 T細胞，此種CD8 T細胞的特性與其他文獻所記載之肝臟駐留記憶性細胞十分相似。此細胞次群對於慢性發炎的B型肝炎病毒轉染模式下的病毒清除扮演非常重要的角色；然而其對於肝臟內免疫反應所扮演之角色甚至在急性發炎的影響尚未明朗。於此論文中，我們利用刀豆蛋白A (Concanavalin A)所誘發的急性肝炎模型來進行探討，類比人體中由於病患本身過度活化的T細胞攻擊肝臟細胞而導致發炎及壞死，最終造成肝硬化的自體免疫性肝炎。當我們事先以抗無唾液酸神經節苷脂 (anti-ASGM1)之抗體對小鼠進行細胞消耗 (depletion) 後再注射刀豆蛋白A，可以觀察到肝炎的狀況無論在血清學或是解剖學的結果上皆受到明顯的抑制。為排除肝臟中另一會大量表現ASGM1的細胞族群，自然殺手細胞 (natural killer cell, NK cell)，我們利用缺少先天性淋巴細胞的NFIL3-/-小鼠進行肝炎的誘發，發現其結果與野生型的小鼠相類似。接著，我們進一步分析此群CD8細胞的表徵，其表現了高量的已知是TRM 細胞的表面標誌 (surface marker)，如CD69、CD44、LFA-1及CXCR3等，為進一步闡明此細胞次群的重要性，我們以另一種組織駐留表面標誌的抗體，anti-CXCR3的抗體對小鼠進行細胞消耗，亦可以觀察到小鼠的肝炎有明顯的改善，顯示應是這群會表現無唾液酸神經節苷脂的CD8 T細胞族群而非自然殺手細胞影響了肝炎的發展。於此肝炎模型下，目前已知是由干擾素γ (Interferon-γ)所介導之Th1反應為主，因此我們分析了有無事先進行anti-ASGM1的細胞消耗對於小鼠體內干擾素γ分泌量的影響，結果顯示，雖然血清中的干擾素γ含量沒有明顯差異，但是在進行血液灌流後的肝臟組織中，干擾素γ的含量在有事先進行細胞消耗的組別中有顯著性的降低；進一步進行質譜流式細胞術分析，我們發現小鼠體內的細胞內染亦可以觀察到肝臟中的T細胞主要於此肝炎模式下的早期(約刀豆蛋白A施打後四小時內)會有明顯的干擾素γ產生，其中又以此ASGM1陽性的CD8肝臟TRM細胞在刀豆蛋白Ａ注射後一小時最為明顯，且事先以anti-ASGM1進行細胞消耗亦可觀察到產生干擾素γ的細胞次群明顯減少。將活化後的ASGM1陽性的CD8肝臟TRM細胞與未活化之免疫細胞共培養亦可促使其效應信息RNA (mRNA)被上調。過繼細胞實驗中，我們再次證明活化後的此群肝臟駐留記憶性細胞可促使肝指數顯著性上升。綜合上述，表現有ASGM1的CD8肝臟TRM細胞在刀豆蛋白A所引起之肝炎模式中應是早期干擾素γ的主要來源，並驅動後續的效應細胞的活化以導致肝炎的發生。除此之外，我們亦透過唾液酸酶處理及細胞過繼實驗證明ASGM1可能作為一重要之肝臟駐留性之指標。" | zh_TW |
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| dc.description.tableofcontents | 口試委員會審定書 ii 誌謝 ii 中文摘要 iii Abstract v Contents vii List of Figures x Chapter 1 Introduction 1 1. Summary of Liver 1 1.1 Structure and physiological function of the liver 1 1.2 Immune response in the liver 1 2. Hepatitis 3 2.1 Autoimmune hepatitis (AIH) 3 3. Concanavalin A (ConA)-induced hepatitis model 4 3.1 Critical subsets of cells participated in ConA-induced hepatitis 5 3.1.1 T cells 5 3.1.2 NKT cells 6 3.1.3 Sinusoid endothelial cells (SECs) and Kupffer cells (KCs) 7 3.2 Crucial cytokines involved in ConA-induced hepatitis 7 3.2.1 Interferon-γ (IFN-γ) 8 4. Tissue resident memory (TRM) cells 9 4.1 Liver resident T cells 10 5. Rationale 12 Chapter 2 Materials and methods 14 1. Materials 14 1.1 Mice 14 1.2 Kits 14 1.3 Antibodies 15 1.4 Antibodies for CyTOF analysis 18 1.5 Chemicals and reagents 19 1.6 Buffer 22 1.7 Primer 23 2. Methods 24 2.1 Concanavalin A hepatitis model establishment 24 2.2 Depletion of intrahepatic lymphocytes (IHLs) in vivo 24 2.3 Assay for plasma transaminase activities 24 2.4 Histological examination 25 2.5 Isolation of murine and human lymphocytes 25 2.6 Culture of T cells 26 2.7 Transwell co-culture system 27 2.8 Flow cytometric analysis lymphocytes 27 2.8.1 Surface marker staining 27 2.8.2 Intracellular staining 28 2.9 Assay for cytokine levels determination 29 2.10 Single cell mass cytometry (CyTOF) 29 2.10 Quantitative PCR analysis 30 2.11 Adoptive transfer 31 2.12 Statistical analysis 31 Chapter 3 Results 33 1. Distinct ASGM1+ CD8+ T cells with liver TRM characteristics existed in the intrahepatic lymphocyte population 33 2. Anti-ASGM1 pre-treatment suppressed ConA-induced hepatitis 35 3. The suppression of ConA-induced hepatitis by anti-ASGM1 pre-treatment was not due to the depletion of NK cells 36 4. Depletion of liver TRM cells through anti-ASGM1 as well as anti-CXCR3 suppressed ConA-induced hepatitis 37 5. Anti-ASGM1 pre-treatment suppressed the liver level of IFN-γ and infiltration of lymphocytes from ConA-induced hepatitis 39 6. ASGM1+ CD8 liver TRM cells were activated in and early manner and produced IFN-γ under ConA administration 41 7. IFN-γ from ASGM1+ liver TRM cells in initial stage was critical in ConA-induced hepatitis 44 8. ASGM1+ CD8 Liver TRM cells were crucial in triggering hepatitis 46 9. ASGM1 was a crucial marker for liver residency 48 10. ASGM1 was expressed by human PBMCs 49 Chapter 4 Discussion 51 1. Contribution of this work 51 2. The effect of antibody depletion varied from the timing of the pre-treatment 52 3. The detailed mechanism of the interaction among ASGM1+ CD8 liver TRM cells and other intrahepatic lymphocytes should be further characterized 54 4. The TCR repertoire and detailed gene profiles of ASGM1+ CD8 liver TRM cells still remained unclear 56 5. Whether ASGM1 alone could serve as a liver homing and resident marker 58 Chapter 5 Figures 60 Chapter 6 Reference 91 | |
| dc.language.iso | en | |
| dc.subject | 質譜流式細胞術 | zh_TW |
| dc.subject | 自體免疫性肝炎 | zh_TW |
| dc.subject | 刀豆蛋白A | zh_TW |
| dc.subject | 無唾液酸神經節苷脂 | zh_TW |
| dc.subject | 組織駐留記憶性T細胞 | zh_TW |
| dc.subject | CD8 T細胞 | zh_TW |
| dc.subject | 干擾素γ | zh_TW |
| dc.subject | Mass Cytometry (CyTOF) | en |
| dc.subject | Autoimmune hepatitis | en |
| dc.subject | Concanavalin A | en |
| dc.subject | Asialo-GM1 | en |
| dc.subject | Tissue resident memory T cells | en |
| dc.subject | CD8 T cell | en |
| dc.subject | Interferon-γ | en |
| dc.title | 表現無唾液酸神經節苷脂之肝臟駐留CD8T細胞為刀豆蛋白A所誘導之小鼠急性肝炎模式下的重要引發者 | zh_TW |
| dc.title | Asialo-GM1+ Liver Resident CD8 T Cells Serve as A Crucial Initiator in Acute Hepatitis Model Induced by Concanavalin A | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 楊宏志(Hsin-Tsai Liu),朱清良(Chih-Yang Tseng) | |
| dc.subject.keyword | 自體免疫性肝炎,刀豆蛋白A,無唾液酸神經節苷脂,組織駐留記憶性T細胞,CD8 T細胞,干擾素γ,質譜流式細胞術, | zh_TW |
| dc.subject.keyword | Autoimmune hepatitis,Concanavalin A,Asialo-GM1,Tissue resident memory T cells,CD8 T cell,Interferon-γ,Mass Cytometry (CyTOF), | en |
| dc.relation.page | 99 | |
| dc.identifier.doi | 10.6342/NTU202102197 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
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