Improved Murine-MHC-Deficient HLA-Transgenic NOD-Mouse Models for Type 1 Diabetes Therapy Development.
Diabetes 2018 Feb 22 [Epub ahead of print]
DK46266, DK95735, OD020351, CA034196, DK064315, DK094327, AI19225
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 non-classical 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 utilized 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 non-classical 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 Feb 22 [Epub ahead of print]
Racine, Jeremy; Stewart, Isabel; Ratiu, Jeremy; Christianson, Gregory J.; Lowell, Emily; Helm, Kelsay; Allocco, Jennifer; Maser, Richard S.; Chen, Yi-Guang; Lutz, Cathleen M; Roopenian, Derry C.; Schloss, Jennifer; DiLorenzo, Teresa P; and Serreze, David V., "Improved Murine-MHC-Deficient HLA-Transgenic NOD-Mouse Models for Type 1 Diabetes Therapy Development." (2018). Faculty Research Ahead of Print. 73.