INSERM U1016, Institut Cochin, Paris, France.
Faculté de Médecine René Descartes, Université Paris Descartes, Paris, France.
Diabetes. 2018 Sep;67(9):1816-1829. doi: 10.2337/db18-0202. Epub 2018 Jul 2.
Key requirements in type 1 diabetes (T1D) are in setting up new assays as diagnostic biomarkers that will apply to prediabetes, likely T-cell assays, and in designing antigen-specific therapies to prevent T1D development. New preclinical models of T1D will be required to help with advancing both aims. By crossing mouse strains that lack either murine MHC class I and class II genes and insulin genes, we developed YES mice that instead express human HLA-A*02:01, HLA-DQ8, and insulin genes as transgenes. The metabolic and immune phenotype of YES mice is basically identical to that of the parental strains. YES mice remain insulitis and diabetes free up to 1 year of follow-up, maintain normoglycemia to an intraperitoneal glucose challenge in the long-term range, have a normal β-cell mass, and show normal immune responses to conventional antigens. This new model has been designed to evaluate adaptive immune responses to human insulin on a genetic background that recapitulates a human high-susceptibility HLA-DQ8 genetic background. Although insulitis free, YES mice develop T1D when challenged with polyinosinic-polycytidylic acid. They allow the characterization of preproinsulin epitopes recognized by CD8 and CD4 T cells upon immunization against human preproinsulin or during diabetes development.
在 1 型糖尿病 (T1D) 中，关键要求是建立新的检测方法作为诊断生物标志物，这些标志物将适用于糖尿病前期，可能是 T 细胞检测方法，并设计针对抗原的治疗方法以预防 T1D 的发展。需要新的 T1D 临床前模型来帮助实现这两个目标。我们通过交叉缺乏鼠 MHC 类 I 和 II 基因和胰岛素基因的小鼠品系，开发了 YES 小鼠，这些小鼠表达的是人 HLA-A*02:01、HLA-DQ8 和胰岛素基因作为转基因。YES 小鼠的代谢和免疫表型与亲本品系基本相同。在长达 1 年的随访中，YES 小鼠仍然没有胰岛炎和糖尿病，在长期范围内对腹腔内葡萄糖挑战保持正常血糖，具有正常的β细胞质量，并对常规抗原表现出正常的免疫反应。这种新模型旨在评估在遗传背景上对人胰岛素的适应性免疫反应，该遗传背景再现了人类高易感性 HLA-DQ8 遗传背景。尽管没有胰岛炎，YES 小鼠在接受聚肌苷酸-聚胞苷酸挑战时会发展为 T1D。它们允许在针对人前胰岛素进行免疫接种或在糖尿病发展期间对 CD8 和 CD4 T 细胞识别的前胰岛素表位进行特征描述。
