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  本文關鍵詞：STZ誘導1型糖尿病模型免疫耐受機制異常的研究　出處：《吉林大學》2005年博士論文　論文類型：學位論文

  更多相關文章： 免疫耐受 1 型糖尿病 CD4+CD25+調(diào)節(jié)性T 細胞 異位基因表達

【摘要】：為了進一步揭示自身免疫耐受機制在防止自身免疫病和建立免疫自穩(wěn)中的作用,本文應用多次低劑量STZ 注射誘導的糖尿病(MLDS-DM)模型作為研究對象,從中樞和外周免疫兩方面,全面、系統(tǒng)地探討自身耐受機制異常在自身反應性糖尿病發(fā)生中的作用。 結果顯示:1、模型鼠表現(xiàn)典型的1 型糖尿病(T1DM)癥狀和胰島炎,是一較為理想的模擬人類T1DM 的動物模型。2、模型鼠存在自身抗體和特異性T 細胞增殖能力升高,表明自身免疫應答參與疾病發(fā)生; 并且模型鼠IFNγ優(yōu)勢分泌,呈Th1 優(yōu)勢應答。3、模型鼠CD4~+胸腺和脾細胞中具有免疫調(diào)節(jié)作用的CD4~+CD25~+胸腺細胞和CD4~+CD25~+Treg水平降低,說明模型鼠存在中樞和外周耐受機制異常。4、在胸腺方面,還表現(xiàn)為胸腺萎縮、胰島素特異性胸腺細胞增殖能力升高和糖尿病相關和非相關自身抗原Insulin 和PLP 的胸腺異位基因表達低下。說明模型鼠胸腺功能異�？赡苁菍е伦陨矸磻猅 細胞和CD4~+CD25~+Treg 的胸腺選擇異常的原因。 因此,本文可以得出以下結論: 1. MLDS-DM 是細胞免疫介導的自身免疫病,尤其Th1 優(yōu)勢應答導致病理性免疫損傷。 2. 模型鼠存在外周和中樞耐受機制缺陷,二者共同參與疾病發(fā)生。表現(xiàn)為自身反應T 細胞和CD4~+CD25~+Treg 胸腺選擇和外周水平異常。 3. 胸腺異位基因表達異�？赡苁菍е伦陨矸磻猅 細胞和CD4~+CD25~+ Treg 胸腺選擇異常的主要原因。 本實驗為MLDS-DM 模型的更廣泛應用提供實驗依據(jù);并為應用CD4~+CD25~+Treg 臨床治療T1DM 提供基礎,其作為誘導免疫耐受的有效手段之一,具有潛在臨床應用前景,值得進一步應用性研究。
[Abstract]:In order to further reveal the role of autoimmune tolerance mechanism in the prevention of autoimmune diseases and the establishment of immune autostability. The MLDS-DM model of diabetes induced by multiple low dose STZ injection was used as the research object. To investigate systematically the role of abnormal self-tolerance mechanism in the development of self-reactive diabetes mellitus. The results showed that the model mice showed typical type 1 diabetes mellitus (T1DM) symptoms and islet inflammation, which was an ideal animal model of human T1DM. Autoantibodies and specific T cell proliferation were found in the model rats, indicating that the autoimmune response was involved in the pathogenesis of the disease. Moreover, IFN 緯 was secreted preferentially in the model rats, showing a Th1 dominant response of 3. 3. The levels of CD4 ~ CD25 ~ Thymocytes and CD4 ~ CD25 ~ Treg in CD _ 4 ~ ~ thymus and spleen cells of model rats were decreased. The results showed that the model rats had abnormal central and peripheral tolerance mechanisms, and thymus atrophy was also found in thymus. Increased Proliferation of Insulin-specific thymocytes and Diabetes Mellitus related and unrelated autoantigens Insulin and PLP. These results suggest that abnormal thymus function may be the cause of abnormal selection of thymocytes and CD _ 4 ~ CD _ 25 ~ Treg. Therefore, this paper can draw the following conclusions: 1. MLDS-DM is an autoimmune disease mediated by cellular immunity, especially the dominant response of Th1 leads to pathological immune damage. 2. There were defects in peripheral and central tolerance mechanisms in the model rats. Both of them were involved in the pathogenesis of the disease, which were characterized by autoresponse T cells, thymus selection and peripheral abnormality of CD4 ~ CD25 ~ Treg. 3. Abnormal expression of thymic ectopic genes may be the main cause of abnormal selection of thymocytes and CD _ 4 ~ CD _ 25 ~ Treg. This experiment provides experimental basis for the wider application of MLDS-DM model. It provides the basis for the clinical treatment of T1DM by CD4 ~ CD25- Treg. As one of the effective means of inducing immune tolerance, CD4 ~ CD25 ~ Treg has a potential clinical application prospect. It is worthy of further applied research.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2005
【分類號】：R392

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本文編號：1441600