胰岛炎
生物
点头
CD8型
人性化鼠标
主要组织相容性复合体
点头老鼠
T细胞受体
T细胞
转基因
细胞毒性T细胞
胰岛素原
人类白细胞抗原
免疫学
转基因小鼠
细胞生物学
自身免疫
免疫系统
抗原
胰岛素
基因
遗传学
体外
内分泌学
作者
Jeremy J. Racine,Adel Misherghi,Jennifer R. Dwyer,Richard S. Maser,Elvira Forte,Olivia Bedard,Susanne Sattler,Alberto Pugliese,Laurie G. Landry,Colleen M. Elso,Maki Nakayama,Stuart I. Mannering,Nadia Rosenthal,David Serreze
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2023-10-25
卷期号:211 (12): 1792-1805
被引量:1
标识
DOI:10.4049/jimmunol.2300303
摘要
Abstract In an effort to improve HLA-“humanized” mouse models for type 1 diabetes (T1D) therapy development, we previously generated directly in the NOD strain CRISPR/Cas9-mediated deletions of various combinations of murine MHC genes. These new models improved upon previously available platforms by retaining β2-microglobulin functionality in FcRn and nonclassical MHC class I formation. As proof of concept, we generated H2-Db/H2-Kd double knockout NOD mice expressing human HLA-A*0201 or HLA-B*3906 class I variants that both supported autoreactive diabetogenic CD8+ T cell responses. In this follow-up work, we now describe the creation of 10 new NOD-based mouse models expressing various combinations of HLA genes with and without chimeric transgenic human TCRs reactive to proinsulin/insulin. The new TCR-transgenic models develop differing levels of insulitis mediated by HLA-DQ8–restricted insulin-reactive T cells. Additionally, these transgenic T cells can transfer insulitis to newly developed NSG mice lacking classical murine MHC molecules, but expressing HLA-DQ8. These new models can be used to test potential therapeutics for a possible capacity to reduce islet infiltration or change the phenotype of T cells expressing type 1 diabetes patient-derived β cell autoantigen-specific TCRs.
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