Faculty Collaboration Database

Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 2018 May;67(5):923-935

Date

02/24/2018

Pubmed ID

29472249

Pubmed Central ID

PMC5909999

DOI

10.2337/db17-1467

Scopus ID

2-s2.0-85046031203 (requires institutional sign-in at Scopus site)   8 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-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-K^d and H2-D^b classical class I variants either individually or in tandem (cMHCI^-/-). Ablation of the H2-A^g7 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.

Author List

Racine JJ, Stewart I, Ratiu J, Christianson G, Lowell E, Helm K, Allocco J, Maser RS, Chen YG, Lutz CM, Roopenian D, Schloss J, DiLorenzo TP, Serreze DV

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CRISPR-Cas Systems
Diabetes Mellitus, Type 1
Disease Models, Animal
HLA-A2 Antigen
HLA-B Antigens
Histocompatibility Antigens Class I
Humans
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, Transgenic
beta 2-Microglobulin