IL-17與CD40配體的協同作用以及QT間隔延長對糖尿性腎病變的長期影響

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题名:	IL-17與CD40配體的協同作用以及QT間隔延長對糖尿性腎病變的長期影響 The role of synergistically IL-17 with CD40 ligand and QT prolong in the chronicity of diabetic nephropathy
作者:	郭慧亮;Hyey-Liang Kuo
贡献者:	臨床醫學研究所博士班
关键词:	糖尿病腎病變;間白素17;心電圖異常;Advanced glycation end-products;CD4+IL-17+ T cell;diabetic nephropathy;IL-17;CD40L;QTc prolongation
日期:	2016-12-26
上传时间:	2018-01-15 09:24:45 (UTC+8)
出版者:	中國醫藥大學
摘要:	背景：在糖尿病腎病變的初期可以在病理切片上看到發炎細胞浸潤，因此浸潤的T細胞和足細胞之間的交互作用可能對糖尿病腎病變的發炎及組織重組有著重要的影響。首先我們套討IL-17 和CD40 配體(CD40L)在糖尿病腎病變的角色，其次在心電圖中QT間隔延長會提高血液透析病患的整體死亡率，但在腹膜透析病人身上的影響卻尚未明瞭。所以我們將研究QT間隔延長對腹膜透析病人的整體死亡率有何影響。方法：總共收錄69個第二型糖尿病患者的病理切片來評估CD4+IL-17+ T 細胞的作用。以CD4+IL-17+ T 細胞的數量和病人的臨床症狀及實驗室檢查結果做關聯性分析。另外在培養的足細胞中加入過度糖化終產物來模擬糖尿病的環境，以探討CD4+IL-17+ T 細胞對糖尿病腎硬化的影響。從2003年收錄306個腹膜透析病人的QT間隔資料並追蹤至2012年底。QT間隔長度大於450 毫秒者認定為QT間隔延長，並且將 QT間隔和整體死亡率及個別疾病死亡率做存活率的統計分析(Cox regression 及 Kaplan-Meier analysis)。結果： CD80 存在於初期糖尿病腎病變但在後期硬化的腎絲球試不存在的。在大部分浸潤的細胞中可以看到CD40 表現量增加，而且足細胞和腎小管上皮細胞也看到CD40表現量增加。 CD40L 只有局部出現在浸潤的細胞中。糖尿病腎病變中可以看到CD4+IL-17+ T細胞，而且CD4+IL-17+ T細胞和病人腎絲球過濾率的退化有關。在糖尿病腎病變的組織中IL-17A 的濃度增加而且也和病人腎絲球過濾率的退化有關。在活體中，IL-17 和CD40L 兩者共同增加 IL-6, MCP-1, RANTES, TGF-β1, 和 NF-κB 的產生。過度糖化終產物會使培養中的足細胞增加IL-17A, CD40, 和 TGF-β1 的產量。使用單株抗體阻斷IL-17 可以減少CD40 和 TGF-β1的產生並且穩定培養中的足細胞。在306個腹膜透析病人中，有196 (64%)個病人的QT間隔是延長的。QT間隔延長的發生率是9.7 /每100個病人-年，而和心臟有關的死亡率為 5.6 /每100個病人-年。根據病人的年紀、性別、是否罹患糖尿病以及糖尿病的時間來調整後，發現QT間隔延長增加腹膜透析病人的整體死亡率，危險機率[hazard ratio (HR)] 是 1.59倍 [95% 信賴區間 (CI): 1.06-2.39, p = 0.03] ；增加了心因性死亡率(HR: 1.66, 95% CI: 1.00-2.78, p = 0.05) 。更長的QT間隔(> 500 ms, 450-500 ms, 和 < 450 ms) 對整體死亡率(p = 0.03, log-rank test) 及心因性死亡率(p = 0.05, log-rank test) 有更大的影響。結論： IL-17 和 CD40L 共同導致糖尿病腎病變的發炎和組織重組。QT間隔延長和腹膜透析病人的年紀及糖尿病程有關而且影響了整體死亡率。 Background. Early stages of diabetic nephropathy (DN) are characterised by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. We first aimed at exploring the role of IL-17 and CD40 ligand (CD40L) in DN. Secondly, prolonged QT interval is associated with all-cause mortality in HD patients. It is unknown if prolonged QT interval is associated with all-cause mortality in peritoneal dialysis (PD) patients. So, we investigated the association of prolonged QT interval and all-cause mortality in chronic PD patients. Setting & Participants. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+IL-17+ T cells. The number of CD4+IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+IL-17+ T cells in renal sclerosis. The QT intervals were measured in 2003 and all patients were followed to Dec 2012. A prolonged QT interval was defined as a QT interval > 450 ms. The association of prolonged QT interval with all-cause and cardiac-specific mortality was analyzed using Cox regression and Kaplan-Meier analysis. Results. CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was observed in most infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+IL-17+ T cells were found in DN, and the number of CD4+IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, MCP-1, RANTES, TGF-β1, and NF-κB production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40, and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes. In total 306 patients, 196 (64%) patients had prolonged QT interval. The incidence density rate was 9.7 per 100 persons-years for all-cause mortality and 5.6 for cardiac specific mortality in patients with prolonged QT interval. Prolonged QT interval was associated with all-cause mortality with a hazard ratio (HR) of 1.59 [95% confidence interval (CI): 1.06-2.39, p = 0.03] and cardiac mortality (HR: 1.66, 95% CI: 1.00-2.78, p = 0.05) with adjustments for age, gender, diabetes, and vintage of dialysis. Longer QT interval (> 500 ms, 450-500 ms, and < 450 ms) was significantly associated with a worse overall survival (p = 0.03, log-rank test) and cardiac mortality free survival (p = 0.05, log-rank test). Conclusions. IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN. Prolonged QT interval was associated with all-cause and cardiac mortality in patients on peritoneal dialysis. The association is independent of patient’s age and diabetes.
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