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標題: | 以小鼠模式探討第一型輔助型T細胞和IFN-γ在原發性膽道硬化症的角色 The Roles of Type I Helper T cells and IFN-γ in a Mouse Model of Primary Biliary Cirrhosis |
作者: | Bi-Jhen Syu 許碧珍 |
指導教授: | 莊雅惠(Ya-Hui Chuang) |
關鍵字: | 肝臟自體免疫疾病,原發性膽道硬化症,IFN-γ,Th1細胞,CD4 T細胞, Liver autoimmune disease,Primary biliary cirrhosis,IFN-γ,Th1 cells,CD4 T cells, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 原發性膽道硬化症(Primary biliary cirrhosis;PBC)為膽道受破壞導致膽汁鬱積甚至肝硬化的慢性肝臟自體免疫疾病。先前研究指出PBC病人血清中IFN-γ表現比起健康的人顯著增加,肝臟內亦可測得PDC-E2專一性輔助性T細胞浸潤。在不同PBC動物模式下也證實Th1細胞及IFN-γ參與在PBC病程,但如何作用於PBC尚未清楚。本研究探討Th1細胞和IFN-γ在PBC所扮演的角色及其作用機轉。我們使用先前實驗室建立的2-OA-OVA誘發PBC之小鼠模式,分析Th1細胞和IFN-γ在此PBC小鼠模式之表現,發現PBC小鼠肝臟中IFN-γ基因表現量以及PBC小鼠第四週血清IFN-γ的表現量均明顯升高。以細胞內染色方法分析PBC小鼠肝臟單核細胞分泌細胞激素的表現亦發現分泌IFN-γ的CD4 T細胞(Type I helper T cell;Th1)百分比顯著增加。為了釐清IFN-γ及Th1如何調控PBC免疫反應,我們將攜帶IFN-γ基因的Adeno-asoociated virus(AAV)給予小鼠同時誘發小鼠產生PBC,再測量其PBC疾病程度。結果顯示大量IFN-γ會增加PBC小鼠肝臟內免疫細胞浸潤,包括CD4+ T、CD8+ T、B、NK與NKT細胞以及增加屬於Th1且與組織發炎相關的TNF-α基因的表現。同時發現IFN-γ也會使PBC小鼠肝臟抗原呈獻細胞數增加且其MHC class II表現增強,而且Th1細胞數量也顯著增加。由以上實驗結果暗示Th1參與在PBC病程,且IFN-γ會增加抗原呈獻細胞並加強其MHC class II之表現以及促進更多CD4 T細胞分化成Th1細胞並製造更多IFN-γ以引起更多免疫反應,例如活化CD8+ T、B、NK與NKT細胞,最後使PBC肝臟門脈發炎情況變得更嚴重。 Primary biliary cirrhosis (PBC) is a slowly progressive liver-specific autoimmune disease caused by the destruction of small intra-hepatic bile ducts, which leads to cholestasis or even cirrhosis. In patients with PBC, the serum levels of IFN-γ are much higher than healthy people and PDC-E2 specific autoreactive helper T cells could be found in their livers. Previous studies showed that IFN-γ and Th1 cells regulate the immune responses in PBC, but the mechanism remains unclear. By using our previous established 2-OA-OVA immunized mouse model of PBC, we found that liver and serum levels of IFN-γ expression were significantly increased in PBC mice while IL-4 and IL-17 were undetectable. In addition, the percentage of IFN-γ-producing CD4 T cells (Th1 cells) in the liver of PBC mice was significantly increased. To study the effects of Th1 cells and IFN-γ on PBC, we intravenously injected IFN-γ expressing adeno-associated virus (AAV-IFN-γ) to 2-OA-OVA immunized PBC mice and measured the features of PBC in these mice. Results showed that administration of IFN-γ significantly increased liver mononuclear cells including CD4+ T, CD8+ T, B, NK and NKT cells and TNF-α expression. Increased numbers of antigen-presenting cells (APCs) with a higher MHC class II expression were also found in AAV-IFN-γ injected PBC mice. Moreover, the frequency and number of IFN-γ producing Th1 cells were also increased. These results suggest that IFN-γ producing Th1 cells play a role in the pathogenesis of PBC. IFN-γ promotes a higher antigen-presenting capability of APCs and Th1 cell differentiation. Th1 cells produce more IFN-γ to augment immune responses such as activating CD8+ T, B, NK and NKT cells, which then exacerbates portal inflammation of PBC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53919 |
全文授權: | 有償授權 |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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