1型糖尿病(T1DM)进行性胰岛自身免疫损伤、最终胰岛完全丧失出现血糖巨幅波动、频发严重低血糖的脆性糖尿病；非抗原特异性免疫治疗可延缓胰岛免疫损伤进程，抗原特异性免疫治疗可诱导致病性胰岛抗原免疫耐受。近年T细胞表位疫苗免疫治疗研究在自身免疫病、肿瘤和HIV感染等领域相继开展。各种针对单一表位的免疫干预均不足以完全终止免疫损伤进程，原因是T1DM致病性T细胞表位种类多、个体差异大且易出现致病表位扩展。我们假设依据个体致病表位特点而定制T细胞表位疫苗可更好地诱导致病表位免疫耐受，因此我们拟以HLA转基因NOD鼠为研究平台，绘制鼠及人致病性T细胞表位谱及表位扩展特点，应用针对个体的T细胞表位多肽复合物或多肽模拟物疫苗诱导其致病表位免疫耐受，动态观察致病性T细胞等免疫学指标，评估不同表位疫苗修饰方法及免疫干预途径的效果，建立HLA转基因NOD鼠定制化T细胞表位疫苗免疫干预方法，为临床应用打下基础。

Type 1 diabetes (T1DM), characterized by progressive autoimmune islet failure, is doomed to enter into the stage of brittle diabetes, which represents severe glycemic instability, frequent and unpredictable server hypoglycemia. Immunotherapies for T1DM have shown that “non antigen-specific intervention” can delay destruction of islet β-cells while “antigen-specific intervention” can induce immune tolerance of islet autoantigen. In recent years, a new immunotherapy approach by T cell epitope vaccine has been studied in fields of autoimmune diseases, carcinoma as well as HIV infection. However, due to the huge individual heterogeneities in the pathogenic T cell epitopes and epitopes spreading, single epitope targeted immunotherapy could not completely halt the autoimmune progress in T1DM. Therefore, we hypothesize that customized T cell epitope vaccine according to the features of the pathogenic T cell epitopes in individuals may provide superior strategy to induce the pathogenic T cell epitope immune tolerance. Based on HLA transgenic non-obese diabetic (NOD) mice, we intend to map the epitope spectrum and how epitope spreading in NOD mice and human patients. Then we design to induce immune tolerance of pathogenic epitope by the combination of T cell epitope vaccine and epitope peptidomimetics vaccine, dynamically monitoring the immunologic biomarkers to evaluate the therapeutic effect of different modification of epitope vaccine and immunization approaches. Thus, the purpose of the research is to establish the protocol of immunotherapy by individually customized T cell epitope vaccine in HLA transgenic NOD mice and for future clinical translation.