Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development
| Autor: | Isabel Stewart, Teresa P. DiLorenzo, Cathleen M Lutz, Kelsay Helm, Jeremy J. Ratiu, Jennifer Allocco, David V. Serreze, Jeremy J. Racine, Derry C. Roopenian, Yi-Guang Chen, Jennifer Schloss, Emily Lowell, Richard S Maser, Gregory J. Christianson |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism Transgene Antigen presentation Mice Transgenic Human leukocyte antigen Nod Major histocompatibility complex Mice 03 medical and health sciences Mice Inbred NOD HLA-A2 Antigen MHC class I Internal Medicine Animals Humans NOD mice Mice Knockout biology Histocompatibility Antigens Class I Molecular biology Disease Models Animal Diabetes Mellitus Type 1 030104 developmental biology HLA-B Antigens biology.protein Immunology and Transplantation CRISPR-Cas Systems beta 2-Microglobulin CD8 |
| Zdroj: | Diabetes. 67:923-935 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db17-1467 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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