Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development.
Document Type
Article
Publication Date
5-2018
JAX Location
Reprint Collection
JAX Source
Diabetes 2018 May; 67(5):923-935
Volume
67
Issue
5
First Page
923
Last Page
935
ISSN
1939-327X
PMID
29472249
DOI
https://doi.org/10.2337/db17-1467
Grant
DK46266, DK95735, OD020351, CA034196, DK064315, DK094327, AI19225
Abstract
Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m-/- mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8+ T-cell responses mediated by these human class I variants. NOD.β2m-/--A2.1 mice were previously used to identify β-cell autoantigens presented by this human class I variant to pathogenic CD8+ T cells and for testing therapies to attenuate such effectors. However, NOD.β2m-/- mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-Kd and H2-Db classical class I variants either individually or in tandem (cMHCI-/-). Ablation of the H2-Ag7 class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II-/-). NOD-cMHCI-/- mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8+ T-cell development and T1D susceptibility to NOD-cMHCI-/- mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development. Diabetes 2018 May; 67(5):923-935.
Recommended Citation
Racine J,
Stewart I,
Ratiu J,
Christianson GJ,
Lowell E,
Helm K,
Allocco J,
Maser RS,
Chen Y,
Lutz C,
Roopenian DC,
Schloss J,
DiLorenzo T,
Serreze DV.
Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 2018 May; 67(5):923-935
Comments
The authors thank The Jackson Laboratory’s Genome Technologies group, Genetic Engineering Technologies group, Flow Cytometry service, Transgenic Genotyping Core, and Research Animal Facility for technical support on this project. The authors also thank Carl Stiewe and his wife, Maike Rohde, for their generous donation toward T1D research at The Jackson Laboratory, which contributed to this work.