臺灣博碩士論文加值系統

葡萄膜炎意指葡萄膜和視網膜發生發炎反應，若未積極治療則可能導致失明。最近研究報告指出，在葡萄膜炎發生時，T細胞活化並分泌大量的 IFN-γ與IL-17是導致發炎的主要原因。由於PD-L1是抑制T細胞活化的配體，有人指出其能夠抑制T細胞的發炎反應，改善自體免疫疾病。因此本專題以實驗性自體免疫葡萄膜炎 (experimental autoimmune uveitis, EAU)小鼠為動物模式，探討以PD-L1治療EAU小鼠之可行性，並且分析治療前後其免疫反應的差異。目前成功建立可以Dox來調控PD-L1表現的腺相關病毒 (rAAV.tnPD-L1)基因治療平台。實驗結果發現，相較於健康小鼠，EAU小鼠的周邊血及脾臟細胞中具有較多的Th1和Th17；以IRBP刺激脾臟細胞則有大量的IFN-γ與IL-17的分泌，顯示EAU小鼠體內具有大量對IRBP具特異性的Th1及Th17細胞。而我們於視網膜下注射rAAV.tnPD-L1治療EAU小鼠，不論是以臨床發炎症狀評估或是病理組織切片分析，皆發現EAU小鼠眼內的發炎可受到有效的改善，而對IRBP具專一性的免疫反應，例如：IFN-γ與IL-17的分泌量和Th1、Th17活化增生也都明顯下降，同時發現Th1及Th17細胞也有減少的趨勢。這些結果顯示以PD-L1治療可以有效降低EAU小鼠體內具視網膜抗原專一性的Th1及Th17免疫反應，減少浸潤到眼球中的發炎細胞，進而成功控制EAU小鼠眼內發炎的症狀。

Uveitis is a chronic inflammatory eye disease category that affects the uvea and retina and results in vision loss. The inflammation appears to be mainly associated with activation of autoreactive T cells. Many studies have indicated that PD-1 and its ligands (such as PD-L1) negatively regulate immune responses, and interaction between PD-1 and PD-L1 plays a protective role in autoimmune diseases. Therefore, here we sought to develop a PD1-targeting approach to suppress experimental autoimmune uveitis (EAU). Successful construction of rAAV delivery PD-L1 controlled by the tet-ON-inducible system (rAAV.tnPD-L1), was confirmed by in vitro infection study, in which the expression of PD-L1 was significantly increased by Dox adminiatration. EAU mice were induced with interphotoreceptor retinal binding protein (IRBP) peptide, and treated intraocularly with rAAV.tnPD-L1. The results demonstrated that rAAV.tnPD-L1 treatment significantly ameliorated the severity of EAU by reducing the retinochoroidal infiltrates of leukocytes. Percentage of Th1 and Th17 in splenic T cells were both massive reduced following rAAV.tnPD-L1 treatment. Moreover, the proinflammatory cytokines, including IFN-γ and IL-17, and proliferation of IRBP-specific T cells derived from the treated group were both reduced. Our data suggest the administration of PD-L1, attenuating EAU intraocular inflammation mainly through suppressing the proinflammatory cytokine produced by IRBP-specific T cells, may be a promising therapeutic strategy in uveitis.

目錄
指導教授推薦書
口試委員會審定書
長庚大學博碩士論文著作授權書 iii
誌謝 iv
中文摘要 v
Abstract vi
縮寫表 vii
目錄 viii
圖目錄 xi
附錄目錄 xiii
第一章 背景 1
1.1 葡萄膜炎 1
1.2 實驗性自體免疫葡萄膜炎 2
1.3 輔助型T細胞-17 (Th17)與介白素-17 (IL-17) 5
1.4 Program death-1及其配體 (ligand) 9
1.5 研究目的 13
第二章 研究方法 14
2.1 實驗設計 14
2.2 實驗流程 16
2.3 材料方法 17
2.3.1 限制酶作用 17
2.3.2 轉染 17
2.3.3 rAAV製備與純化 17
2.3.4 病毒核酸定量 18
2.3.5 細胞次培養 18
2.3.6 重組腺相關病毒感染 19
2.3.7 細胞外染色 19
2.3.8 細胞內染色 19
2.3.9 Treg染色 20
2.3.10 全蛋白萃取 21
2.3.11 蛋白定量 21
2.3.12 十二烷基硫酸鈉聚丙烯醯胺膠電泳 (Sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 21
2.3.13 西方墨點法 (western blot) 22
2.3.14 免疫小鼠 22
2.3.15 小鼠周邊血採集與前處理 22
2.3.16 石蠟包埋 23
2.3.17 石蠟切片與hematoxylin and eosin染色 23
2.3.18 酵素連結免疫吸附法 (Enzyme-linked immunosorbent assay, ELISA) 24
2.3.19 淋巴球增生分析：氚標記的胸腺嘧啶核甘 (Tritiated thymidine)攝入試驗 25
第三章 結果 26
3.1 建立可調控PD-L1之rAAV系統 26
3.2 建立EAU小鼠模式並探討其體內免疫反應的變化 29
3.3 從臨床症狀與組織結構評估以調控PD-L1治療EAU小鼠之療效 32
3.4 分析PD-L1治療前後EAU小鼠免疫反應的差異 34
3.5 評估PD-L1治療對於EAU小鼠體內具IRBP專一性的免疫反應之影響 36
第四章 討論 38
第五章 參考文獻 44

 
圖目錄
圖一、以限制酶切割確認製備可表現PD-L1的RAAV所需之質體 58
圖二、分析轉染帶有PD-L1質體的3T3細胞株PD-L1的表現量 59
圖三、以即時定量PCR測定RAAV效價 60
圖四、分析感染RAAV.TNPD-L1的3T3細胞株表現PD-L1的比例以及單一細胞PD-L1表現量 61
圖五、分析感染RAAV.TNPD-L1的3T3細胞株PD-L1的總表現量 63
圖六、評估以質體轉染或以RAAV病毒感染之3T3細胞株表現PD-L1的細胞比例差異 65
圖七、PD-1、CD4螢光抗體標記EAU小鼠周邊血之細胞分群 66
圖八、EAU小鼠周邊血白血球中表現PD-1的細胞分析 67
圖九、FOXP3、CD4及CD25螢光抗體標記小鼠周邊血之細胞分群 68
圖十、分析EAU小鼠周邊血白血球中調控型T細胞 69
圖十一、以臨床方法評估EAU小鼠接受PD-L1基因治療後的療效 71
圖十二、以組織病理切片方式評估EAU小鼠眼接受PD-L1基因治療後眼睛復原的情形 73
圖十三、分析接受PD-L1基因治療的EAU小鼠其周邊血白血球表現PD-1的比例 74
圖十四、分析PD-L1基因治療對EAU小鼠周邊血白血球中調控型T細胞的影響 76
圖十五、分析接受PD-L1基因治療的EAU小鼠脾臟細胞中表現PD-1的細胞比例 78
圖十六、分析以PD-L1治療的EAU小鼠脾臟細胞中TREG的比例 80
圖十七、螢光抗體標記小鼠脾臟TH1及TH17之細胞分群 82
圖十八、分析PD-L1治療對EAU小鼠體內的TH1及TH17之影響 83
圖十九、分析PD-L1治療對EAU小鼠脾臟細胞中具IRBP專一性的細胞激素分泌量之影響 85
圖二十、PD-L1治療可降低EAU小鼠脾臟細胞中對IRBP具有專一性的細胞增生 87



 
附錄目錄
附錄一、即時定量PCR引子表 89
附錄二、SDS-PAGE 膠體配方 90
附錄三、SDS-PAGE 及西方墨點法試劑配方 91
附錄四、小鼠眼底發炎程度評估標準 92
附錄五、評估EAU小鼠疾病發展過程及天數 93
附錄六、分析脾臟細胞中Th1和Th17的比例 94
附錄七、偵測對IRBP具有專一性的免疫反應 95
附錄八、以PD-L1對EAU小鼠進行基因治療之流程 96

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