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系統識別號 U0007-0406201323281900
論文名稱(中文) Sorafenib在人類抗原呈現細胞之作用
論文名稱(英文) The effects of sorafenib on human antigen presenting cells
校院名稱 臺北醫學大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Graduate Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 林俊昌
研究生(英文) Jiunn-Chang Lin
學號 D102095010
學位類別 博士
語文別 英文
口試日期 2013-06-04
論文頁數 0頁
口試委員 指導教授-吳志雄
共同指導教授-陳裕仁
委員-黃偉邦
委員-蔡東湖
委員-廖慧芬
委員-楊育正
委員-李居仁
中文關鍵字 自噬作用  樹突細胞  巨噬細胞  移植 
英文關鍵字 sorafenib  autophagy  dendritic cell  macrophage  transplantation 
學科別分類
中文摘要 背景: Sorafenib是一個多重酪氨酸激活脢抑制劑,被研發出來做為抗癌藥物,目前已被用於治療末期肝癌及腎細胞癌。近年有文獻報告Sorafenib會抑制樹突細胞的功能,但其它關於Sorafenib對免疫系統的影響則很少被探討,本研究探討Sorafenib對樹突細胞和巨噬細胞的影響,並以動物模式來驗證Sorafenib在移植醫學的應用。
實驗方法: 樹突細胞和巨噬細胞是從人類周邊血所分離出的CD14+單核細胞演化而來,細胞的存活率以7-AAD方法測試,細胞表面抗原以流式細胞儀檢驗,細胞產生的自噬作用以電子顯微鏡、免疫螢光染色、西方墨點法、流式細胞儀…等方式來驗證,最後以小鼠皮膚移植的動物模式來檢測Sorafenib對移植物存活時間的影響。細胞培養上清液和小鼠血清中的細胞激素以酵素免疫分析法來檢驗。
實驗結果: Sorafenib會有抑制樹突細胞和巨噬細胞存活的效果,樹突細胞在Sorafenib處理後會偏向不成熟狀態,而Sorafenib在樹突細胞和巨噬細胞都會誘發自噬作用。樹突細胞中之mTOR與p70S6K蛋白表現量會被Sorafenib抑制。巨噬細胞的功能(包括CD80的表現、吞噬能力、製造ROS的能力)都會被Sorafenib抑制,而在動物實驗我們也已發現Sorafenib能延長皮膚移植的存活時間,並且在這些老鼠的脾臟中也發現Sorafenib會增加調節性T淋巴球的比例。若以chloroquine來阻斷自噬作用,則Sorafenib延長移植皮膚存活的效果也會降低。
結論: Sorafenib除了原本的抗癌作用之外,也能透過在樹突細胞和巨噬細胞誘發自噬作用,而有潛力作為移植之後的抗排斥藥。
英文摘要 Background: Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on function of dendritic cells (DCs). This study was aimed to examine the effects of sorafenib on DCs and macrophages, the major ontogeny of innate immunity, on inducing autophagy, immunomodulatory activity, and its implication on graft rejection.
Methods: DCs and Macrophages were derived from sorted CD14+ monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by 7-amino-actinomycin D (7-AAD) and flowcytometric analysis. Autophagy was characterized by using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation, and mTOR signaling molecules, as well as immmunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by ELISA.
Results: We found that sorafenib inhibited viability of DCs and macrophages accompanied by morphological changes characteristic of autophagy. Surface markers of DCs also showed immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with down-regulation of phosphorylated mTOR and its downstream substrate p70S6K in DCs. The functions of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. We next performed skin graft model to testify the role of sorafenib-treated antigen presenting cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. The percentage of regulatory T cells in spleen was upregulated in sorafenib-treated mice. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo.
Conclusion: This study suggests that sorafenib, in addition to being an anti-cancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of DCs and macrophages.
論文目次 中文摘要(Abstract in Chinese) ………………………………………………7
英文摘要(Abstract in English) ……………………………………………….8
Introduction ………………………………………………………………….10
Materials and Methods ……………………………………………………...16
Generation of human macrophages and dendritic cells ……………………….16
Number of viable cells ………………………………………………………..16
Flow cytometric analysis for surface markers, acridine orange staining, and reactive oxygen species production …………………………………………..17
Morphological observation ……………………………………………………17
Transmission electronic microscopy ………………………………………….18
Endogenous LC3-B immunofluorescence …………………………………….18
GFP-LC3 immunofluorescence ……………………………………………….18
Western blotting ……………………………………………………………….18
Detection of cytokines produced by MDDCs and macrophages ……………...19
Phagocytosis …………………………………………………………………..19
Skin Transplantation Model …………………………………………………...20
Results …………………………………………………………………………21
Sorafenib affected viability of human macrophages …………………………..21
Sorafenib induced autophagy in human macrophages ………………………...21
Sorafenib suppressed the CD80 expression and function of activated macrophages …………………………………………………………………...22
Sorafenib affected secretion of cytokines of human macrophage ……………..22
Sorafenib inhibited viability and induced acidic vesicular organelles in MDDCs ………………………………………………………………………..22
Validation of sorafenib-induced autophagy in MDDCs ………………………23
Involvement of mTOR pathway in sorafenib-induced autophagy …………….23
Sorafenib-induced autophagy might be a cytoprotective effect ……………….24
Sorafenib suppressed maturation of DC and influenced secretion of cytokines by DCs …………………………………………………………………………….24
Sorafenib prolonged skin allograft survival in mice …………………………24
Discussion ……………………………………………………………………26
Conclusion and Perspective ………………………………………………...38
References …………………………………………………………………...39
Figures ……………………………………………………………………….58
Appendix …………………………………………………………………….86
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