STZ诱导1型糖尿病模型免疫耐受机制异常的研究

发布时间：2018-01-18 16:06

本文关键词：STZ诱导1型糖尿病模型免疫耐受机制异常的研究　出处：《吉林大学》2005年博士论文　论文类型：学位论文

【摘要】：为了进一步揭示自身免疫耐受机制在防止自身免疫病和建立免疫自稳中的作用,本文应用多次低剂量STZ 注射诱导的糖尿病(MLDS-DM)模型作为研究对象,从中枢和外周免疫两方面,全面、系统地探讨自身耐受机制异常在自身反应性糖尿病发生中的作用。结果显示:1、模型鼠表现典型的1 型糖尿病(T1DM)症状和胰岛炎,是一较为理想的模拟人类T1DM 的动物模型。2、模型鼠存在自身抗体和特异性T 细胞增殖能力升高,表明自身免疫应答参与疾病发生; 并且模型鼠IFNγ优势分泌,呈Th1 优势应答。3、模型鼠CD4~+胸腺和脾细胞中具有免疫调节作用的CD4~+CD25~+胸腺细胞和CD4~+CD25~+Treg水平降低,说明模型鼠存在中枢和外周耐受机制异常。4、在胸腺方面,还表现为胸腺萎缩、胰岛素特异性胸腺细胞增殖能力升高和糖尿病相关和非相关自身抗原Insulin 和PLP 的胸腺异位基因表达低下。说明模型鼠胸腺功能异常可能是导致自身反应T 细胞和CD4~+CD25~+Treg 的胸腺选择异常的原因。因此,本文可以得出以下结论: 1. MLDS-DM 是细胞免疫介导的自身免疫病,尤其Th1 优势应答导致病理性免疫损伤。 2. 模型鼠存在外周和中枢耐受机制缺陷,二者共同参与疾病发生。表现为自身反应T 细胞和CD4~+CD25~+Treg 胸腺选择和外周水平异常。 3. 胸腺异位基因表达异常可能是导致自身反应T 细胞和CD4~+CD25~+ Treg 胸腺选择异常的主要原因。本实验为MLDS-DM 模型的更广泛应用提供实验依据;并为应用CD4~+CD25~+Treg 临床治疗T1DM 提供基础,其作为诱导免疫耐受的有效手段之一,具有潜在临床应用前景,值得进一步应用性研究。
[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 纬 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.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R392

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