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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 許秉寧 | |
dc.contributor.author | I-Tsu Chyuan | en |
dc.contributor.author | 全以祖 | zh_TW |
dc.date.accessioned | 2021-06-08T02:38:27Z | - |
dc.date.copyright | 2018-08-01 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-07-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19989 | - |
dc.description.abstract | 腫瘤壞死因子相關凋亡誘導配體 (TRAIL) 可藉由與其受體 (TRAIL receptor) 結合來傳遞促凋亡訊息而造成細胞凋亡。雖然TRAIL實際的生物角色目前仍不清楚,但越來越多證據顯示TRAIL可調節免疫反應與免疫細胞的恆定性,表示TRAIL可能除了誘導細胞凋亡外,也具有免疫調節的功能。然而,在自體免疫疾病中,TRAIL如何調節自體免疫反應目前仍不清楚。在我們的研究中,我們利用發炎性關節炎 (collagen-induced arthritis, CIA) 的動物模式顯示TRAIL可顯著抑制關節發炎的發生與減少關節炎的嚴重度,並且發現TRAIL抑制關節炎並非透過誘導發炎關節內細胞 (T細胞、巨噬細胞、滑膜細胞) 凋亡。相比之下,TRAIL可直接抑制活化後T細胞的增生與細胞激素的產生,顯示可直接抑制T細胞的活化而抑制發炎。此外,在TRAIL受體剔除 (TRAIL receptor knockout) 小鼠在誘導關節炎後,會產生比野生型 (wild-type) 小鼠更嚴重的關節炎,並且TRAIL的抗發炎的效果也消失。因此,我們認為TRAIL可透過非依賴細胞凋亡之路徑而是直接抑制T細胞活化來抑制自體免疫性發炎。為了更進一步闡述在自體免疫疾病中,TRAIL在調節T細胞活化的免疫調節角色與分子機轉,我們使用自體免疫性腦脊髓炎 (experimental autoimmune encephalomyelitis, EAE) 動物模式;結果顯示TRAIL可顯著抑制神經發炎,並且抑制T細胞對神經抗原 (MOG35-55) 的反應性,而此效果依賴於TRAIL受體的訊息傳遞。此外,TRAIL可直接抑制以MOG35-55活化的CD4 T細胞反應,並且利用過繼性轉移 (adoptive transfer) 誘導之自體免疫性腦脊髓炎模式中也發現,經TRAIL處理的MOG35-55 活化CD4 T細胞,可降低神經發炎與疾病嚴重度。我們更進一步也發現,TRAIL受體訊息路徑可抑制活化後CD4 T細胞其近端T細胞受體 (T cell receptor) 相關的酪氨酸激酶 (tyrosine kinases) 之磷酸化。更重要的是,藉由RNA定序 (RNA sequencing) 與轉錄組分析 (transcriptome analysis),我們也發現TRAIL/TRAIL受體之交互作用可抑制T細胞受體下游訊息路徑基因。這些結果表示在自體免疫性發炎中,TRAIL/TRAIL受體之交互作用可調節CD4+ T細胞之活化,並且透過抑制T細胞受體之訊息傳導來直接抑制T細胞的活化,這也意味著TRAIL受體在T細胞之免疫反應中可作為一個免疫管制點 (immune checkpoint) 的角色。我們的研究對於TRAIL在自體免疫性發炎中提供一個非誘導細胞凋亡之免疫調節新機轉,並且為自體免疫疾病治療提供嶄新的治療策略。 | zh_TW |
dc.description.abstract | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis, suggesting an immune-regulatory role of TRAIL besides triggering apoptosis in immune-mediated diseases. However, the immune-regulatory role of TRAIL in regulating autoimmune responses in autoimmune diseases is still not clear. In our study, we created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited activated T cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL-R knockout (TRAIL-R KO) mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R KO mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T cell activation. To further address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases, we used experimental autoimmune encephalomyelitis (EAE) animal model. The results have demonstrated that TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen [myelin oligodendrocyte glycoprotein (MOG)35-55] in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4 T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4 T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. These results indicate that TRAIL/TRAIL-R interaction regulates CD4 T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing autoimmune inflammation and shed light on the development of effective new therapies for autoimmune diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:38:27Z (GMT). No. of bitstreams: 1 ntu-107-Q01421010-1.pdf: 21972980 bytes, checksum: baaa21a06a4cc59fce6c69b99d233490 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iv Table of Contents vi List of Figures xi Abbreviations xv Chapter 1 Introduction 1 1. TRAIL and TRAIL receptors 1 2. TRAIL and apoptosis 4 2.1. TRAIL/TRAIL-R apoptosis signaling pathways 4 2.2. Regulation of TRAIL/TRAIL-R signaling 7 2.3. TRAIL and necroptosis 9 3. TRAIL and its receptors in cancer 9 3.1. TRAIL in the immune surveillance against cancers 11 3.2. Clinical trials using soluble TRAIL or TRAIL-R agonists in cancer therapy 11 4. Biological function of TRAIL 13 4.1. Characterization of the in vivo function of TRAIL 13 4.2. Characterization of the in vivo function of TRAIL-R 14 5. TRAIL in regulation of autoimmune diseases 14 5.1. The role of TRAIL in rheumatoid arthritis 15 5.2. The role of TRAIL in neuroinflammation 16 6. TRAIL in regulation of inflammatory cells 17 6.1. TRAIL in innate immunity 17 6.2. TRAIL in adaptive immunity 18 6.3. TRAIL in T cells 19 6.4. The effect of TRAIL on inflammatory cells in inflammatory arthritis 20 6.5. The effect of TRAIL on inflammatory cells in neuroinflammation 21 7. TRAIL-mediated signaling pathways in T cells 22 8. Rationale and significance 25 Chapter 2 Materials and Methods 26 1. Materials 26 1.1. Animals 26 1.2. Cell lines 26 1.3. Primer and plasmid 27 1.4. Kits 27 1.5. Recombinant protein 29 1.6. Antibodies 29 1.7. Chemicals and reagents 33 1.8. Buffers 36 2. Methods 37 2.1. Purification of TRAIL 37 2.2. Induction of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) and assessment of arthritis severity 38 2.3. Induction of EAE and assessment of neurological severity 39 2.4. Histological analysis 40 2.5. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining 40 2.6. Cleaved caspase-3 immunohistochemistry staining 41 2.7. Measurement of cytokines and chemokines 41 2.8. Analysis of cell apoptosis by flow cytometry 42 2.9. Carboxyfluorescein succinimidyl ester (CFSE) staining 42 2.10. In vitro apoptosis detection 43 2.11. Brain and spinal cord [central nervous system (CNS)] mononuclear cell isolation 43 2.12. IL-17 and IFN-γ enzyme-linked immunospot (ELISpot) assay 44 2.13. Intracellular cytokine assay 44 2.14. Thymidine incorporation assay 45 2.15. Transcriptome analyses 45 2.16. Western blot analysis 46 2.17. Preparation of lipid raft fractions 48 2.18. Intracellular phospho-protein staining for flow cytometry 48 2.19. Generation of MOG35-55-specifc CD4+ T cells and I-Ab MOG35-55 tetramer staining 48 2.20. Co-immunoprecipitation (Co-IP) 49 2.21. In vitro differentiation of induced regulatory T cells (iTregs) 49 2.22. Statistical analysis 50 Chapter 3 Results 51 1. TRAIL significantly reduced the severity and incidence of the joint inflammation and paw swelling in rats with CIA 51 2. TRAIL significantly inhibited the production of proinflammatory cytokines and chemokines in inflammatory arthritis 52 3. Suppression of joint inflammation by TRAIL was not due to the induction inflammatory cell apoptosis 52 4. Suppression of joint inflammation by TRAIL is via TRAIL/TRAIL-receptor interaction 53 5. TRAIL directly inhibits T cell activation by suppressing the T-cell proliferation and cytokine production 54 6. TRAIL suppresses neuroinflammation and autoreactive T cell reactivity in EAE mice 55 7. Suppression of neuroinflammation by TRAIL is dependent on TRAIL-R signaling 56 8. TRAIL directly inhibits MOG35-55-activated T cell activation and suppresses the development of autoimmune inflammation in adoptive transfer-induced EAE 56 9. Downregulated TCR signaling-associated genes in TRAIL-treated EAE mice 58 10. TRAIL/TRAIL-R interaction suppresses phosphorylation of proximal TCR signaling molecules and inhibits T cell activation 59 Chapter 4 Discussion 62 1. TRAIL inhibits inflammation in autoimmune diseases 62 2. TRAIL suppresses autoimmune inflammation via an apoptosis-independent manner in inflammatory arthritis 63 3. TRAIL inhibits activated T cell responses in inflammatory arthritis 64 4. TRAIL inhibits autoimmune inflammation in experimental autoimmune encephalomyelitis 65 5. TRAIL/TRAIL-R interaction controls autoimmune inflammation in experimental autoimmune encephalomyelitis 66 6. TRAIL/TRAIL-R interaction down-regulates autoreactive T cell responses 67 7. The inhibitory function of TRAIL on autoreactive T cells is through suppressing TCR signaling pathway 68 8. TRAIL-R serves as a novel immune checkpoint in T cell responses 70 9. Conclusion 71 Chapter 5 Reference 72 Chapter 6 Figures 101 Chapter 7 Appendix 155 Publication List 160 | |
dc.language.iso | en | |
dc.title | TRAIL調控T細胞活化與自體免疫發炎之非凋亡誘導性免疫調節角色 | zh_TW |
dc.title | A novel immune-regulatory role of TRAIL in T cell activation and autoimmune inflammation via an apoptosis-independent pathway | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 賈景山 | |
dc.contributor.oralexamcommittee | 謝世良,林琬琬,楊宏志,林世昌 | |
dc.subject.keyword | 腫瘤壞死因子相關性細胞凋亡誘導配體,腫瘤壞死因子相關性細胞凋亡誘導配體受體,T 細 胞訊息傳導,細胞凋亡,脂筏, | zh_TW |
dc.subject.keyword | TRAIL,TRAIL receptor,T cell signaling,apoptosis,lipid raft, | en |
dc.relation.page | 161 | |
dc.identifier.doi | 10.6342/NTU201801666 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2018-07-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
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