臺灣博碩士論文加值系統

類風溼性關節炎（Rheumatoid Arthritis, RA）是種慢性自體免疫疾病，全球約有1%的人口受其影響，主要病徵包括關節的滑膜發炎、軟骨侵蝕與關節結構破壞等症狀。其中發炎反應被認為在類風濕性關節炎中案演重要關鍵，吸引免疫細胞並釋放細胞激素進而影響關節與全身系統。而長期的慢性發炎容易引發諸多併發症，如骨質疏鬆與心血管疾病等，也是造成類風濕性關節患者死亡率居高不下的原因。目前仍無方法可以完全治癒類風濕性關節炎，臨床治療的策略為減緩疼痛與延阻關節炎的惡化。本實驗室自行開發的克弗爾肽在過去研究中發現在心血管疾病、骨質疏鬆與肺發炎疾病中皆展現出良好的減緩與治療功效。故本實驗進一步將克弗爾肽應用於類風濕性關節炎動物模式中，欲探討克弗爾肽是否能減緩發炎與抑制骨質流失。研究中使用6週齡的Lewis大鼠進行佐劑誘導關節炎，將大鼠分為：(1)正常鼠對照組、(2)佐劑誘導關節炎疾病對照組、(3)佐劑誘導關節炎+低劑量克弗爾肽實驗組、(4)佐劑誘導關節+高劑量克弗爾肽實驗組、(5)佐劑誘導關節炎+生物製劑藥物正對照組。在佐劑誘導後15天開始進行連續兩週治療，實驗結束後犧牲大鼠採集踝關節組織進行後續分析。結果顯示關節炎臨床評估中高劑量克弗爾肽能有效減緩關節炎的症狀。在超音波影像、X光片與組織病理切片中亦顯示在高劑量克弗爾肽治療後能減少滑膜炎與骨質流失。而在活體螢光影像中則顯示克弗爾肽有降低MMP表現量的趨勢。在組織mRNA含量分析中，高劑量克弗爾肽能有效減少巨噬細胞分泌的TNF-α、IL-1β與IL-6等發炎因子，且能降低RANKL/OPG的比值，抑制蝕骨細胞的活化。組織蛋白含量分析的部分則能降低NF-κB途徑的活性，減少下游產生TNF-α。綜合上述結果，克弗爾肽可以透過減少組織中NF-κB途徑的活性與降低巨噬細胞分泌發炎因子來減緩關節中的發炎反應與骨骼侵蝕作用。因此相當具有潛力作為類風濕性關節炎患者的新穎治療物質。

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of people in the world. The pathological characteristics include synovial inflammation, bone erosion, and joint structure damages. Furthermore, the inflammatory responses of rheumatoid arthritis attract immune cells to aggregate in joints and release cytokines to cause bone erosion. Chronic inflammation can lead to many complications, such as osteoporosis and cardiovascular disease, which is also the reason for the high mortality rate of rheumatoid arthritis patients. Our previous studies have shown that kefir peptides, derived from kefir fermented product, can reduce cardiovascular disease, osteoporosis and lung inflammation, but the anti-inflammatory effect of kefir peptides on RA is still unknown. To investigate the anti-inflammatory effect of kefir peptides on RA, kefir peptides were used to treat the rat model of adjuvant-induced arthritis (AIA). The animals were divided into five groups, normal, arthritis- induced alone (Mock), arthritis-induced and supplemented with low-dose kefir peptides (KPs-L), arthritis-induced high-dose kefir peptides (KPs-H) and Tofacitinib drug. When the arthritis onset, each group was treated with water (Mock), kefir peptides or Tofacitinib, respectively. After 14 days treatment, the ankle joint tissue were collected for analysis. In the clinical arthritis assessment, result showed that the KPs-H group has lower arthritis score than the Mock group, and the ultrasonography, radiograph and histological demonstrated that decreased severity of the synovitis and bone erosion of the ankle joint after high dose kefir peptides treatment. In non invasion in vivo imaging system (IVIS) fluorescence images also showed all kefir peptides groups have less MMP expression than the arthritis-induced mock group. Moreover, the administration of kefir peptides also decrease inflammation in ankle joint by decreaseing the mRNA expression of TNF-α, IL-1β, IL-6, MMP-13 and RANKL/OPG ratio. In protein analysis, high dose kefir peptides has reduce the NF-κB pathway and TNF-α expression. These results indicated that kefir peptides may have an anti-inflammatory effect and reduce the bone erosion of ankle joint by decrease macrophage product inflammation cytokines. This study confirmed that kefir peptides is a potentially promising substance for the treatment of rheumatoid arthritis.

摘要 i
Abstract ii
目次 iii
圖次 vi
表次 vii
壹、緒論 1
貳、文獻探討 2
一、自體免疫疾病 (Autoimmune disease) 2
(一)免疫耐受性 (Immune tolerance) 2
(二)常見的自體免疫疾病種類 3
二、類風濕性關節炎 (Rheumatoid Arthritis, RA) 7
(一)關節的組成與基本構造 7
(二)類風濕性關節炎疾病的發展過程 11
(三)類風濕性關節炎罹病風險 13
(四)現今的治療策略 14
三、類風濕性關節炎參與的發炎反應 17
(一)先天性免疫(Innate immunity) 17
(二)適應性免疫(Adaptive Immunity) 19
(三)免疫反應中參與的發炎途徑與細胞激素 21
四、類風濕性關節炎動物疾病模式 24
(一)佐劑誘導關節炎(adjuvant-induced arthritis, AIA) 24
(二)二型膠原蛋白誘導關節炎(collagen type II induced arthritis, CIA) 25
(三)鏈球菌細胞壁誘導關節炎(Streptococcal cell wall arthritis, SCW) 26
五、生物醫學影像 28
(一)常見的醫學影像技術 28
(二)藥物開發研究活體分子影像技術 31
六、克弗爾(Kefir)發酵產物 33
(一)克弗爾的組成成分 33
(二)克弗爾的保健功效 33
七、研究動機與目的 37
參、材料與方法 38
一、建立關節炎動物模式 38
(一)實驗動物品系來源與飼養條件 38
(二)佐劑誘導關節炎動物模式 38
二、實驗流程 40
(一)實驗架構規劃 40
(三)試驗材料製備 43
三、動物犧牲與採集組織樣品 43
(一)犧牲前器具準備 43
(二)血清 43
(三)胸腺 44
(四)脾臟 44
(五)後腳組織 44
(六)其他 44
四、X光片影像分析 45
五、非侵入式螢光活體分子影像系統 (non invasion in vivo imaging system, IVIS) 45
(一)MMPsense 750 FAST製備與注射 45
(二)IVIS操作與參數設定 46
(三)影像訊號分析與定量 46
六、超音波掃瞄影像 46
(一)前置準備與儀器開啟 46
(二)老鼠擺位與探頭掃描角度 47
(三)滑膜炎分級評估 47
七、組織病理學分析 48
(一)組織前處理 48
(二)石蠟包埋與切片 48
(三)蘇木紫-伊紅染色 49
(四)組織病理評分 49
(五)免疫組織化學染色 49
八、mRNA表現量分析 53
(一)樣品RNA萃取 53
(二)RNA定量、DNA去汙與合成cDNA 53
(三)定量即時聚合酶鏈鎖反應 (Quantitative real time polymerase chain reaction, qRT-PCR) 54
九、蛋白質表現量分析 57
(一)樣品總蛋白質萃取 57
(二)蛋白質濃度測定 57
(三)西方墨點法 57
十、統計分析與繪圖軟體 61
肆、結果 62
一、建立佐劑誘導關節炎動物模式與克弗爾肽最適治療時間 62
(一)佐劑誘導關節炎動物模式發病變化 62
二、克弗爾肽治療對於佐劑誘導關節炎大鼠之生理參數與臨床關節評估 64
(一)體重變化 64
(二)臨床關節炎評分 64
(三)踝關節腫脹變化 65
(四)後腳發炎照片 65
三、評估克弗爾肽治療對於組織病理與切片改善功效 70
(一) X光片影像 70
(二)超音波影像 70
(三)IVIS系統螢光影像 71
(四)組織切片H＆E染色與病理評分 71
四、 評估克弗爾肽治療對於發炎因子濃度與發炎途徑活化程度變化 78
(一) mRNA表現量分析 78
(二)蛋白表現量分析 80
伍、討論 84
一、建立佐劑誘導關節炎動物模式之材料方法與發病率 84
二、活體醫學影像對於佐劑誘導關節炎動物模式病變追蹤與評估 84
三、克弗爾肽對於佐劑誘導關節炎之功效評估 85
(一)克弗爾肽對於佐劑誘導關節炎之抗發炎功效 85
(二)克弗爾肽對於佐劑誘導關節炎之骨保護功效 85
(三)克弗爾肽對於佐劑誘導關節炎治療之可能作用機制 86
陸、結論 88
柒、參考文獻 89

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