
Humanized mice engrafted with peripheral blood mononuclear cells from HLA-DR15-positive multiple sclerosis patients develop spontaneous and induced inflammatory lesions in the brain and spinal cord, predominantly composed of CD8 T cells.


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Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMC) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus (EBV) reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord grey matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.

### Competing Interest Statement

The authors have declared no competing interest.

Spontaneous human CD8 T cell and EAE-inducible human CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis PBMC humanized mice

spontaneous-and-induced-cd8-t-cell-lesions-in-the-central-nervous-system-of-hla-dr15-positive-multiple-sclerosis-patient-derived-humanized-mice


Spontaneous and Induced CD8 T Cell Lesions in the Central Nervous System of HLA-DR15-Positive Multiple Sclerosis Patient-Derived Humanized Mice
