臺灣博碩士論文加值系統

全身性紅斑狼瘡 (Systemic lupus erythemotosus，SLE) 是一種全身性自體免疫疾病。有研究指出SLE病人體內有較高的氧化壓力及PGE2的生成，維生素E為體內必需且有效的抗氧化劑，並能調節prostaglandins的代謝因此可能影響免疫功能，T輔助細胞細胞激素的分泌及細胞凋亡等。本研究目的即在探討維生素E與自體免疫疾病發展之關係。以MRL/lpr自體免疫鼠為動物模式，將88隻鼠齡為12週大的小鼠依體重及尿蛋白程度隨機分成四組：Control (AIN-76 basal diet)、E5 (AIN-76 建議量5倍的維生素E)、E7.5 (AIN-76 建議量7.5倍的維生素E)、E10 (AIN-76 建議量10倍的維生素E)。至鼠齡5個月大時犧牲每組8隻小鼠，未犧牲的小鼠則持續餵養並觀察生命期。
結果顯示，5個月大犧牲的小鼠，各組間生長狀況及飼料利用效率皆無差異。器官相對重量方面，E7.5組及E10組的肝重顯著較控制組重，另外E10組心臟也較控制組重。雖然血漿、肝臟及腎臟中a-tocopherol濃度，添加維生素E的三組，顯著高於控制組，且與劑量成正比。但維生素E的補充並不影響肝臟及腎臟中脂質過氧化 (TBARS值) 的狀況。對PGE2的影響，以脾臟細胞培養24小時，在裂殖素刺激下，補充維生素的E三組，PGE2分泌顯著低於控制組，E5組之肝臟中PGE2生成亦顯著低於控制組。但維生素E的添加並未影響MRL/lpr鼠腹腔細胞的PGE2的分泌，尿液中PGE2代謝物bicyclo PGE2及6-keto PGF1a亦無顯著差異。脾臟細胞培養24小時，Th1細胞激素分泌量方面，無論有無添加裂殖素，IL-2分泌在E10組顯著較低；而Th2細胞激素分泌量，在裂殖素刺激下，E10組IL-4、IL-10有顯著增高，IL-6則有降低的情形。腹腔細胞在有添加裂殖素時，E10組的IL-6分泌量顯著高於各組。血漿中的自體抗體生成在E10組期IgM型抗體顯著較高，生命期也有一致的結果，四組小鼠的平均壽命並無顯著差異，但維生素E10組有較低的趨勢 (p=0.082)。
因此，維生素E之添加，雖然可降低小鼠脾臟細胞PGE2的生成，但並未藉由減少氧化壓力或發炎反應與影響T輔助細胞平衡的調控來減緩病情與延長生命期。其中IL-2因維生素E添加而降低的情形，在病情發展可能扮演重要的角色。因此藉由細胞外添加方式，探討維生素E對於自體免疫鼠脾臟細胞發育過程，細胞激素之分泌，及其對病程的影響。以不同年齡MRL/lpr鼠及BALB/c鼠的脾臟體外培養下，發現維生素E之添加顯著降低脾臟IL-2之生成，且抑制程度與劑量成正比，同時進行RT-PCR檢測，發現維生素E會抑制IL-2 mRNA的表現。因此，對IL-2分泌量遠低於正常鼠之MRL/lpr鼠而言，維生素E之添加反而不利其免疫調節，故對SLE患者在高量維生素E之攝取上宜應謹慎，並仍有待進一步的研究。

The MRL/lpr mice develop a syndrome similar to human systemic lupus erythematosus (SLE), including production of autoantibodies and formation of immune complexes to cause tissue damage and then renal failure. The purpose of this study was to investigate the effect of vitamin E supplementation on autoimmune disease. MRL/lpr female mice was randomly divided into four groups and when they are fed on an AIN-76 diet containing 5% fresh soybean oil (control)；supplemented with vitamin E at 5 times (E5)、7.5 times (E7.5) and 10 times (E10) of AIN-76 respectively, starting at the age of 3 month. After 2 months experimental diet, eight mice were killed for analysis. The rest of mice were followed up for proteinuria and life span.
The results showed that the growth curve and food efficiency were not significantly different. Supplementation with all-rac-a-tocopheryl acetate elevated the a-tocopherol content in plasma, liver and kidney. However, TBARS values of liver and kidney were not significantly different. Though vitamin E supplementation decreased the PGE2 production of splenocyte, the Th1 cytokine such as IL-2 secretion from splenocyte were significantly lower in E10 group and Th2 cytokine such IL-4、IL-10 were significantly higher. Therefore supplementation with vitamin E neither reduced the autoantibody production nor prolong the life span. The same result was observed in cell cultured that IL-2 secrete has been inhibited by vitamin E supplemented in medium. The IL-2 mRNA expression was also found to be lower when vitamin E was supplemented in the medium. The inhibition effect of vitamin E on IL-2 secretion may be not helpful to Th-2 prone autoimmune disease and remain of interest to be investigated.

【目錄】
中文摘要1
英文摘要3
第一章 緒論
第一節 前言.............................................................................6
第二節 文獻回顧....................................................................8
1.2.1 自體免疫疾病之簡介.....................................................8
一、 免疫系統自體耐受性之建立.......................................8
二、 自體免疫疾病的分類....................................................8
1.2.2 全身性紅斑狼瘡簡介......................................................9
一、 疾病特徵..........................................................................9
二、 臨床診斷.........................................................................10
三、 致病因素.........................................................................12
四、 臨床治療.........................................................................13
五、 動物模式.........................................................................13
1.2.3 全身性紅斑狼瘡之相關研究.........................................15
一、 免疫系統之調節.............................................................15
二、 細胞激素..........................................................................17
三、 前列腺素...........................................................................18
四、 氧化壓力...........................................................................22
五、 膳食油脂...........................................................................23
六、 動情激素...........................................................................25
七、 限制熱量攝取..................................................................26
八、 細胞凋亡...........................................................................26
1.2.4 維生素E...............................................................................29
一、 維生素E之簡介.................................................................29
二、 維生素E對細胞的調節....................................................32
三、 維生素E對免疫的調節....................................................33
四、 維生素E與細胞凋亡之關係............................................34
第二章 餵食維生素E對於MRL/lpr自體免疫鼠病情之影響
第一節 實驗動機及假說.......................................................37
第二節 材料與方法................................................................38
2.2.1 動物飼養...............................................................................38
2.2.2 飼料配製...............................................................................39
2.2.3 實驗流程...............................................................................41
第三節 病情指標之測定.............................................................42
2.3.1 尿蛋白測定...........................................................................42
2.3.2 血清樣本的收集...................................................................42
2.3.3 血清中抗雙股DNA抗體的測定.........................................42
2.3.4 血清中抗心磷脂抗體的測定..............................................44
第四節 動物犧牲及樣品收集與分析.........................................45
2.4.1 腹腔細胞之取得及培養.......................................................45
2.4.2 脾臟細胞之取得與培養.......................................................46
2.4.3 細胞激素分泌量的測定.......................................................47
2.4.4 PGE2分泌量的測定...............................................................49
2.4.5 組織均質..................................................................................49
2.4.6 肝臟和腎臟中外因性PGE2含量的測定.49
2.4.7 TBA反應物含量的測定.........................................................50
2.4.8 組織維生素E含量的測定.......................................................51
2.4.9 尿液之分析................................................................................52
一、 Creatinine測定............................................................................52
二、 尿中bicyclo- PGE2之測定........................................................53
三、 尿中6-keto PGE1α之測定......................................................53
2.4.10 統計方法..................................................................................54
第五節 結果與討論............................................................................55
2.5.1 維生素E對MRL/lpr雌鼠生長狀況之影響..............................55
一、 體重變化....................................................................................55
二、 飼料攝取....................................................................................55
三、 器官重量....................................................................................59
2.5.2 維生素E對MRL/lpr雌鼠體內氧化壓力抗
一、 氧化能力狀態之影響...............................................................59
二、 組織中α-tocopherol的濃度......................................................59
三、 TBARS含量.................................................................................62
2.5.3 維生素E對MRL/lpr雌鼠體內PGE2生合成之影響................62
一、 免疫細胞PGE2的分泌量..........................................................64
二、 肝臟及腎臟中PGE2的分泌量..................................................64
三、 尿中代謝產物bicyclo- PGE2及6-keto PGE-1α的含量.........66
2.5.4 維生素E對MRL/lpr雌鼠免疫細胞分泌細胞激素之影響....70
一、 腹腔巨噬細胞分泌的細胞激素..............................................70
二、 脾臟細胞分泌的細胞激素.......................................................72
.2.5.5 維生素E對MRL/lpr雌鼠病情指標之影響..............................72
一、 尿蛋白測定.................................................................................75
二、 抗雙股DNA抗體的測定...........................................................75
三、 抗心磷脂抗體的測定................................................................77
四、 生命期觀察.................................................................................77
第三章 維生素E對MRL/lpr雌鼠脾臟細胞體外培養之影響
第一節 實驗動機.................................................................................83
第二節 實驗設計.................................................................................83
第三節 材料與方法.............................................................................84
3.3.1 體外培養......................................................................................84
3.3.2 細胞激素分泌量測定................................................................84
3.3.3 IL-2 mRNA含量測定..................................................................84
一、 脾臟細胞RNA抽取....................................................................85
二、 RNA之電泳分析........................................................................85
三、 脾臟細胞RNA樣品處理...........................................................86
四、 聚合脢連鎖反應引子 (primer) 的設計與合成.86
五、 半定量反轉錄聚合脢連鎖反應..............................................87
六、 DNA之電泳分析........................................................................88
七、 結果處理及判讀........................................................................88
第四節 結果與討論...........................................................................89
3.4.1 脾臟細胞體外培養細胞激素之分泌.......................................89
3.4.2 脾臟細胞 IL-2 mRNA之表現.....................................................93
第四章 總結.........................................................................................97
第一節 綜合討論.................................................................................97
第二節 結論.........................................................................................99
第五章 參考文獻.................................................................................101
圖目錄
圖1-1 自體免疫疾病中免疫細胞的交互作用..........................................................................................................16
圖1-2 Th1和Th2細胞所釋放的細胞激素間之互相調節.........................................................................................19
圖1-3 花生四烯酸經由cycloxygenase及lipoxygenase之代謝途徑............................................................................21
圖1-4 ROS在全身性紅斑狼瘡的發炎反應所扮演的角色.....................................................................................24
圖1-5 兩大類維生素E的基本結構..............................................................................................................................31
圖2-1 餵食不同含量維生素E之MRL/lpr雌鼠生長曲線..........................................................................................56
圖2-2 餵食不同含量維生素E之MRL/lpr雌鼠每日平均攝食量.............................................................................57
圖2-3 餵食不同含量維生素E之MRL/lpr雌鼠腹腔細胞之IL-6分泌量的影響...71
圖2-4 餵食不同含量維生素E之MRL/lpr雌鼠脾臟細胞之Th1細胞激素IL-2、IFN-γ分泌量的響影..............73
圖2-5 餵食不同含量維生素E之MRL/lpr雌鼠脾臟細胞之Th2細胞激素IL-4、IL-6、IL-10分泌量的影響......74
圖2-6 餵食不同含量維生素E之MRL/lpr雌鼠出現尿蛋白症狀的發生率.............................................................76
圖2-7 餵食不同含量維生素E之MRL/lpr雌鼠血清中抗雙股DNA抗體含量的影響...........................................78
圖2-8 餵食不同含量維生素E之MRL/lpr雌鼠血清中抗心磷脂抗體含量的影響................................................79
圖2-9 餵食不同含量維生素E之MRL/lpr雌鼠存活率的影響...................................................................................80
圖3-1 小鼠脾臟細胞初代培養之Th1細胞激素IL-2分泌量的影響.........................................................................90
圖3-2 小鼠脾臟細胞初代培養之Th1細胞激素IFN-g分泌量的影響......................................................................91
圖3-3 小鼠脾臟細胞初代培養之Th2細胞激素IL-4分泌量的影響.........................................................................92
圖3-4 DNA電泳分析BALB/c及MRL/lpr脾臟細胞IL-2 mRNA及b-actin經RT-PCR後之表現情形......................95
圖4-1 維生素E對自體免疫疾病影響的可能機轉....................................................................................................100
表目錄
表 2-1 實驗飼料組成........................................................................................................................................................40
表 2-2 餵食不同含量維生素E之MRL/lpr雌鼠在五個月大犧牲時之體重、體重增 加量、攝食量、飼料利用效率的
影響..........................................................................................................................................................................58
表 2-3 餵食不同含量維生素E之MRL/lpr雌鼠在五個月大犧牲時之器官重量及相對器官重量的影響...........60
表 2-4 餵食不同含量維生素E之MRL/lpr雌鼠肝臟、腎臟、脾臟及血漿中α- tocopherol濃度的影響..............61
表 2-5 餵食不同含量維生素E之MRL/lpr雌鼠肝臟及腎臟TBARS含量的影響.......................................................63
表 2-6 餵食不同含量維生素E之MRL/lpr雌鼠腹腔及脾臟細胞之PGE2分泌量的影響.........................................65
表 2-7 餵食不同含量維生素E之MRL/lpr雌鼠肝臟、腎臟中PGE2生成量的影響..................................................67
表 2-8 餵食不同含量維生素E之MRL/lpr雌鼠肝臟、腎臟中bicyclo- PGE2含量的影響.........................................68
表 2-9 餵食不同含量維生素E之MRL/lpr雌鼠尿中bicyclo- PGE2及6-keto PGF1α含量的影響.............................69
表 3-1 以Semi-quantitative RT-PCR 方法比較不同劑量維生素E對MRL/lpr及BALB/c小鼠脾臟細胞IL-2 mRNA表現之
影響............................................................................................................................................................................96

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