【摘要】：自身免疫耐受是指免疫系統(tǒng)對自身抗原的特異性免疫無反應(yīng)狀態(tài),是維持免疫自穩(wěn)的重要機(jī)制。自身耐受主要是通過中樞耐受和外周耐受兩大機(jī)制來維持。為了進(jìn)一步揭示機(jī)體自身免疫耐受在維持自身穩(wěn)定、調(diào)節(jié)免疫平衡、防止自身免疫病中的作用,本文分別應(yīng)用多次低劑量STZ注射誘導(dǎo)的糖尿病(MLDS-DM)模型和自發(fā)1型糖尿病(T1DM)的NOD小鼠,在疾病的不同發(fā)展階段,全面系統(tǒng)地探討了自身免疫耐受機(jī)制異常在自身免疫性糖尿病發(fā)生中的作用。 一、STZ誘導(dǎo)的糖尿病模型 首先,為了探討不同劑量STZ誘導(dǎo)糖尿病模型的機(jī)制,尋找STZ誘導(dǎo)1型糖尿病模型的最佳劑量及T1DM發(fā)生的免疫應(yīng)答特點。檢測了糖尿病模型的相關(guān)指標(biāo)及細(xì)胞和體液免疫功能。在此基礎(chǔ)上,為了研究糖尿病模型中樞和外周耐受異常是STZ直接作用還是間接作用的結(jié)果,本實驗采用在STZ誘導(dǎo)糖尿病模型同時補充胰島素,以探討STZ誘導(dǎo)的糖尿病模型中樞和外周免疫耐受異常的機(jī)制。 結(jié)果表明: 1.小劑量STZ(20 mg/kg·bw)和中等劑量STZ(40 mg/kg·bw)誘導(dǎo)產(chǎn)生細(xì)胞和體液免疫應(yīng)答參與的自身免疫性糖尿病(T1DM),但以40 mg/kg·bw STZ誘導(dǎo)的T1DM的效果最佳;而大劑量STZ(80mg/kg·bw)直接破壞胰島β細(xì)胞,誘導(dǎo)小鼠產(chǎn)生II型糖尿病。 2.STZ以某種機(jī)制直接作用于胸腺,影響了T細(xì)胞在胸腺內(nèi)的選擇、分化,導(dǎo)致中樞耐受異常,從而引起T1DM的發(fā)生。另外,STZ直接破壞胰島β細(xì)胞,胰島素分泌水平降低,造成胸腺細(xì)胞的營養(yǎng)障礙,間接損傷胸腺的結(jié)構(gòu)和功能,進(jìn)一步打破了中樞耐受機(jī)制,促進(jìn)了自身免疫病的發(fā)展。
[Abstract]:Autoimmune tolerance refers to the specific immune response of the immune system to autoantigens, and is an important mechanism to maintain immune homeostasis. Self-tolerance is mainly maintained through central tolerance and peripheral tolerance. In order to further reveal the role of autoimmune tolerance in maintaining self-stability, regulating immune balance and preventing autoimmune diseases, The diabetic (MLDS-DM) model induced by multiple low dose STZ injection and NOD mice with spontaneous type 1 diabetes mellitus (T1DM) were used at different stages of disease development. The role of abnormal mechanism of autoimmune tolerance in the occurrence of autoimmune diabetes mellitus was discussed comprehensively and systematically. First of all, in order to explore the mechanism of diabetes induced by different doses of STZ, the best dose of STZ induced type 1 diabetes model and the immune response characteristics of T1DM were found in the diabetic model induced by STZ. The related indexes and cellular and humoral immune function of diabetic model were detected. On this basis, in order to study whether the abnormal central and peripheral tolerance of diabetic model was the direct or indirect effect of STZ, insulin was supplemented in STZ induced diabetic model at the same time. To investigate the mechanism of abnormal central and peripheral immune tolerance in diabetic model induced by STZ. The results show that: 1. Low dose STZ (20 mg/ kg 路bw) and medium dose STZ (40 mg/ kg 路bw) induced autoimmune diabetes mellitus (T1DM) with cellular and humoral immune responses, but 40 mg/ kg 路bw STZ induced T1DM was the best. High dose STZ (80mg/ kg 路bw) directly destroyed islet 尾 cells and induced type II diabetes in mice. 2.STZ acts directly on the thymic gland by some mechanism, which affects the selection and differentiation of T cells in the thymic gland, and leads to abnormal central tolerance, which leads to the occurrence of T1DM. In addition, STZ directly destroys islet 尾 cells, reduces insulin secretion, causes nutritional disorders of thymocytes, indirectly damages the structure and function of thymocytes, further breaks the mechanism of central tolerance and promotes the development of autoimmune diseases.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2006
【分類號】：R392;R587.1

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相關(guān)期刊論文 前1條

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本文編號：2475941