A humanized mouse model to study type 1 diabetes. Mus musculus

The clinical management of type 1 diabetes (T1D) faces the lack of fully predictive biomarkers and of antigen-specific therapies to prevent its development. From a therapeutic standpoint, preclinical modls of T1D have fallen short of directly translating into the human. To circumvent this limitation, we developed a new mouse model that is deficient for expression of murine major histocompatibility complex class I, class II and of murine insulin genes and instead expresses HLA-A*02:01, the high susceptibility HLA-DQ8 molecule and human insulin. The metabolic and immune phenotype of these mice is basically identical to that of the parental strains. Upon expression of B7.1 under the control of the rat insulin promoter, these mice develop T1D along with a T-lymphocyte response to human preproinsulin epitopes spanning the whole autoantigen sequence. This new model will allow evaluating peptide-based immunotherapy that may directly apply to human T1D. Overall design: We analysed 2 YES mice to compare with one NOD mouse and one C57BL/6 mouse as controls. Finaly, we have 4 samples.

1型糖尿病（type 1 diabetes, T1D）的临床管理面临两大核心局限：缺乏完全有效的预测生物标志物，也缺乏可阻断其发病的抗原特异性疗法。从治疗角度而言，当前1型糖尿病的临床前模型难以直接向人类临床转化。为突破这一局限，我们构建了一种新型小鼠模型：该模型缺失小鼠主要组织相容性复合体I类、II类（murine major histocompatibility complex class I/II）以及小鼠胰岛素基因的表达，转而表达HLA-A*02:01、高易感型HLA-DQ8分子与人胰岛素（human insulin）。该小鼠的代谢与免疫表型与亲本品系基本一致。当在大鼠胰岛素启动子（rat insulin promoter）的调控下表达B7.1时，这些小鼠会患上1型糖尿病，并伴随针对覆盖整个自身抗原序列的人胰岛素原表位的T淋巴细胞应答。这一新型模型可用于评估可直接应用于人类1型糖尿病的肽类免疫疗法（peptide-based immunotherapy）。
整体实验设计：我们对2只YES小鼠进行了分析，并以1只NOD小鼠与1只C57BL/6小鼠作为对照，最终共获得4份样本。