DEVELOPMENT OF A NOVEL HUMANIZED ANIMAL MODEL OF IDDM

描述（改编自申请人的摘要）：本研究的总体目标 项目是开发一种新型的1型糖尿病（IDDM）动物模型， 与人类疾病密切相关，并使用这种“人性化”的动物模型， 以确定易感性的分子基础。 IDDM 是一种多基因疾病，研究证实， 定义遗传易感性是编码在MHC区域内， 6号染色体。 虽然OR基因座被认为是重要的，但目前 数据表明，DQ区域与胰岛素依赖型糖尿病的联系更为密切， 在IDDM患者中最常见的单倍型是DQ 8单倍型。 的 最近开发的缺乏鼠II类的人HLA-DQ 8转基因小鼠 初步研究表明，DQ 8分子可以有效地 呈递谷氨酸脱羧酶（GAD）肽并引发体液和 对GAD肽的细胞免疫应答。 T细胞系特异性 对于GAD肽（p17），其与科萨基病毒具有序列同源性 蛋白质也产生了。 为了研究DQ 8分子， 自发性疾病发展模型，I-A（g7），非肥胖糖尿病（NOD） MHC II类被人HLA-DQ 8取代，而不改变任何其他疾病 相关基因，如MHC I类基因座。 新的“人性化”NOD模式 将使我们能够表征DQ 8分子在呈现中的独特特征， 潜在致病性GAD肽，如肽17（氨基酸 249-268）及其来源于科萨基病毒的分子模拟肽 蛋白质在自发性糖尿病发展模型中的作用。 的长期目标 该项目是为了产生“人源化”NOD/SCID小鼠，以探索 初诊糖尿病患者T淋巴细胞功能研究 患者（携带DQ 8）在1型糖尿病发病机制中的作用。 本研究 为进一步研究胰岛素依赖型糖尿病的免疫发病机制提供了新的手段 希望能有助于制定具体的干预措施。

DESCRIPTION (adapted from applicant's abstract): The overall goal of this project is to develop a novel animal model of type 1 diabetes (IDDM) which closely parallels the human disease and to use this "humanized" animal model to identify the molecular basis for the susceptibility to the disease. IDDM is a polygenic disease and studies have confirmed that the main locus defining genetic susceptibility is encoded within the MHC region on chromosome 6. Although the OR locus is thought to be important, current data suggest that the DQ regions are more closely linked to IDDM and the most common haplotype seen in patients with IDDM is the DQ8 haplotype. The recently developed human HLA-DQ8 transgenic mouse lacking murine class II molecules and preliminary studies show that DQ8 molecules can efficiently present glutamic acid decarboxylase (GAD) peptides and elicit humoral and cellular immune responses toward the GAD peptides. T cell lines specific for a GAD peptide (p17), which shares sequence homology with Coxsackie virus protein have also been generated. To study the DQ8 molecules in a spontaneous disease development model, l-A(g7), the non-obese diabetic (NOD) MHC class II is replaced by human HLA-DQ8 without altering any other disease associated genes, such as MHC class I loci. The new "humanized" NOD model will allow us to characterize unique features of DQ8 molecules in presenting potentially etiopathogenic GAD peptides, such as peptide 17 (amino acid 249-268) and its molecular mimic peptide derived from Coxsackie virus protein in a spontaneous diabetes development model. The long-term goal of this project is to generate "humanized" NOD/SCID mice in order to explore the role of human T lymphocytes isolated from newly diagnosed diabetic patients (bearing DQ8) in the pathogenesis of type 1 diabetes. This study will provide a novel means of studying the immunopathogenesis of human IDDM and hopefully will help to develop specific interventions.