Improved murine MHC-deficient HLA transgenic NOD mouse models for type 1 diabetes therapy development

Jeremy J. Racine, Isabel Stewart, Jeremy Ratiu, Greg Christianson, Emily Lowell, Kelsay Helm, Jennifer Allocco, Richard S. Maser, Yi Guang Chen, Cathleen M. Lutz, Derry Roopenian, Jennifer Schloss, Teresa P. Dilorenzo, David V. Serreze

Research output: Contribution to journalArticle

4 Scopus citations

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-A02:01 or HLA-B39:06 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.

Original languageEnglish (US)
Pages (from-to)923-935
Number of pages13
JournalDiabetes
Volume67
Issue number5
DOIs
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Racine, J. J., Stewart, I., Ratiu, J., Christianson, G., Lowell, E., Helm, K., Allocco, J., Maser, R. S., Chen, Y. G., Lutz, C. M., Roopenian, D., Schloss, J., Dilorenzo, T. P., & Serreze, D. V. (2018). Improved murine MHC-deficient HLA transgenic NOD mouse models for type 1 diabetes therapy development. Diabetes, 67(5), 923-935. https://doi.org/10.2337/db17-1467