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- Title
Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development.
- Authors
Racine, Jeremy J.; Stewart, Isabel; Ratiu, Jeremy; Christianson, Greg; Lowell, Emily; Helm, Kelsay; Allocco, Jennifer; Maser, Richard S.; Yi-Guang Chen; Lutz, Cathleen M.; Roopenian, Derry; Schloss, Jennifer; DiLorenzo, Teresa P.; Serreze, David V.; Chen, Yi-Guang
- 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.
- Subjects
TREATMENT of diabetes; TYPE 1 diabetes; HLA histocompatibility antigens; MAJOR histocompatibility complex; DISEASE susceptibility; TRANSGENIC mice; T cells; ANIMAL disease models; ANIMAL experimentation; BIOLOGICAL models; BLOOD proteins; COMPARATIVE studies; GENE expression; GLOBULINS; HISTOCOMPATIBILITY antigens; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; HLA-B27 antigen; EVALUATION research
- Publication
Diabetes, 2018, Vol 67, Issue 5, p923
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-1467