Improved Murine-MHC-Deficient HLA-Transgenic NOD-Mouse Models for Type 1 Diabetes Therapy Development.

Jeremy Racine, The Jackson Laboratory
Isabel Stewart
Jeremy Ratiu, The Jackson Laboratory
Gregory J. Christianson, The Jackson Laboratory
Emily Lowell, The Jackson Laboratory
Kelsay Helm, The Jackson Laboratory
Jennifer Allocco
Richard S. Maser, The Jackson Laboratory
Yi-Guang Chen
Cathleen M Lutz, The Jackson Laboratory
Derry C. Roopenian, The Jackson Laboratory
Jennifer Schloss
Teresa P DiLorenzo
David V. Serreze, The Jackson Laboratory


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]