The Role of IL-2 in Autoimmune Diabetes

IL-2 在自身免疫性糖尿病中的作用

• 批准号: 7169203
• 负责人: Richard A. Flavell
• 金额: $ 31.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169203
• 关键词: 129 Mouse; Alleles; Animal Model; Antigens; Autoimmune Diabetes; Autoimmune Process; Candidate Disease Gene; Cell Death; Characteristics; Chromosome Mapping; Chromosomes, Human, Pair 3; Collaborations; Development; Diabetes Mellitus; Disease; Event; Excision; Frequencies; Gene Targeting; Generations; Genes; Genetic; Histocompatibility Antigens Class II; Human; IL2 gene; Immune system; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Islets of Langerhans; Kinetics; Knock-in Mouse; Maps; Mouse Strains; Mus; Non obese; Predisposition; Resistance; Role; Suppressor-Effector T-Lymphocytes; Susceptibility Gene; T-Lymphocyte; Technology; Testing; base; diabetic; embryonic stem cell; gene replacement; interleukin-17C; interleukin-21

DESCRIPTION (provided by applicant): Type 1 insulin-dependent diabetes mellitus is caused by an autoimmune attack on the islets of Langerhans. The susceptibility to this disease is determined both genetically and by environmental events. The elucidation of the underlying mechanisms of this disease has been greatly facilitated by the mapping of genes conferring susceptibility or resistance to diabetes in humans. Further, the availability of animal models, including the non-obese diabetic (NOD) mouse has made it possible to perform fine mapping of the corresponding mouse genes. Idd3 is a critical diabetes-susceptibility gene, which has profound effects on development of disease. NOD mice carrying an Idd3 gene from the diabetes-resistant B6 mouse show a substantially reduced incidence of insulitis and diabetes as well as greatly retarded kinetics of disease development. The Idd3 locus has been mapped to a 780 kb region of chromosome 3. The most likely candidate gene in this region is the IL-2 gene. This gene shows several structural differences between alleles that are derived from resistant or susceptible strains of mice. However, definitive evidence for or against a role of IL-2 has not yet been obtained, since it has not been possible until recently to target genes in the NOD genetic background. In this study we will establish gene knock-in technology on the NOD genetic background by using NOD/129 F1 ES (embryonic stem) cells, which we have recently found to be very effective in all the steps of gene targeting. Specifically, to establish or refute a role of IL-2 in T1 DM, we will use gene targeting to replace the IL-2 gene of the NOD mouse with the IL-2 gene of the diabetes-resistant B6 mouse. We hypothesize that the NOD allele of IL-2 confers susceptibility to diabetes in one of two ways. First, IL-2 is required for antigen induced cell death (AICD) and we propose that AICD in NOD mice is deficient as a result of a defective IL-2 gene. Our second hypothesis proposes that suppressor (also called regulatory) T-cells, which are IL-2 dependent, are defective in the NOD mouse as a result of an IL-2 deficiency in this strain. We will utilize our IL-2 knock-in mice to test these two mutually nonexclusive hypotheses.

描述（由申请人提供）：1 型胰岛素依赖型糖尿病是由胰岛自身免疫攻击引起的。对这种疾病的易感性是由遗传和环境事件决定的。赋予人类糖尿病易感性或抵抗力的基因图谱极大地促进了对该疾病的潜在机制的阐明。此外，包括非肥胖糖尿病（NOD）小鼠在内的动物模型的可用性使得对相应小鼠基因进行精细定位成为可能。 Idd3是一个关键的糖尿病易感基因，对疾病的发展具有深远的影响。携带来自抗糖尿病 B6 小鼠的 Idd3 基因的 NOD 小鼠显示出胰岛素炎和糖尿病的发病率显着降低，并且疾病发展的动力学大大延迟。 Idd3 基因座已被定位到 3 号染色体的 780 kb 区域。该区域最有可能的候选基因是 IL-2 基因。该基因显示出源自抗性或易感小鼠品系的等位基因之间的一些结构差异。然而，尚未获得支持或反对 IL-2 作用的明确证据，因为直到最近才可能针对 NOD 遗传背景中的基因。在本研究中，我们将利用NOD/129 F1 ES（胚胎干细胞）细胞在NOD遗传背景上建立基因敲入技术，我们最近发现该技术在基因打靶的所有步骤中都非常有效。 具体来说，为了建立或反驳IL-2在T1 DM中的作用，我们将使用基因打靶将NOD小鼠的IL-2基因替换为抗糖尿病B6小鼠的IL-2基因。我们假设 IL-2 的 NOD 等位基因通过以下两种方式之一赋予糖尿病易感性。首先，IL-2是抗原诱导细胞死亡（AICD）所必需的，我们认为NOD小鼠中的AICD是由于IL-2基因缺陷而缺乏的。我们的第二个假设提出，由于 NOD 小鼠品系中 IL-2 缺陷，因此依赖 IL-2 的抑制性（也称为调节性）T 细胞在 NOD 小鼠中存在缺陷。我们将利用 IL-2 敲入小鼠来测试这两个互不排斥的假设。