定制化T细胞表位疫苗免疫治疗1型糖尿病研究

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.

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。

项目背景：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。.主要内容：获得T1DM 致病性T 细胞表位谱及其随病程进展的动态变化，建立致病性T 细胞动态监测体系及评估系统；根据致病性T细胞表位谱特点，尝试个体化定制T 细胞表位疫苗诱导抗原特异性免疫耐受的方法和途径，结合抗CD20 单抗研究工作基础，联合抗CD20 单抗非特异性免疫治疗和T 细胞表位疫苗特异性免疫治疗，探索最佳、有效的免疫学干预方案。.重要结果及其意义：建立新发1型糖尿病患者、非新发1型糖尿病患者和1型糖尿病患者一级亲属三个队列，从人和动物模型（NOD. β 2mnull.HHD鼠）两个层面完成T1DM自身抗原T细胞表位库的建立和优化，分析了致病性T细胞与T1DM发病年龄等临床特征之间的关系，建立一个兼具高敏感性及高特异性的自身抗原T细胞表位库。对中国汉族人群中胰岛自身抗体阳性的T1D病例进行GWAS分析，首次报道了三个在中国人群中鉴定出的易感位点，为未来个体化精准干预提供了切实可行的指标。利用抗CD20单抗（利妥昔单抗）、定制化致病性T细胞表位多肽、细胞免疫等多种方法初步探索1型糖尿病非特异性和特异性免疫治疗的效果。

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