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）：类型1胰岛素依赖性糖尿病是由对Langerhans胰岛的自身免疫性攻击引起的。通过遗传和环境事件确定对这种疾病的敏感性。通过赋予人类易感性或抗性易感性或抗性的基因的映射，阐明了这种疾病的潜在机制。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映射成为可能。 IDD3是一种关键的糖尿病敏感性基因，对疾病的发展具有深远的影响。从抗糖尿病的B6小鼠中携带IDD3基因的NOD小鼠显示出胰岛炎和糖尿病的发生率大大降低，并且疾病发育的动力学大大降低。 IDD3基因座已被映射到3染色体3的780 Kb区域。该区域最有可能的候选基因是IL-2基因。该基因显示出源自小鼠的抗性或易感性菌株的等位基因之间的几种结构差异。但是，尚未获得针对IL-2作用或反对IL-2作用的确定证据，因为直到最近才能在点头遗传背景中靶向基因。在这项研究中，我们将通过使用点数/129 F1 ES（胚胎干）细胞在点头遗传背景上建立基因敲击技术，我们最近发现，在基因靶向的所有步骤中，它们都非常有效。 具体而言，为了建立或反驳IL-2在T1 DM中的作用，我们将使用抗糖尿病抗性B6小鼠的IL-2基因代替NOD小鼠的IL-2基因。我们假设IL-2的点头等位基因以两种方式之一赋予对糖尿病的敏感性。首先，抗原诱导的细胞死亡（AICD）需要IL-2，我们建议NOD小鼠中的AICD由于有缺陷的IL-2基因而缺乏。我们的第二个假设提出，IL-2依赖性的抑制（也称为调节的）T细胞在该菌株中IL-2缺乏的结果中在NOD小鼠中有缺陷。我们将利用我们的IL-2敲击小鼠来测试这两个相互判断性的假设。