Spontaneous and inducible CD8 T cell lesions in the brain and spinal cord of HLA-DR15-positive MS PBMC humanized mice

Abstract

Autoimmune diseases of the central nervous system 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 novel therapeutics. We describe a humanized mouse model with several key MS features. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMC) from MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. DR13-positive MS PBMC mice developed low levels of graft versus host disease (GVHD) and no CNS inflammation. Both DR15 MS and DR15 HI mice developed spontaneous and EAE-inducible infiltration of CNS barriers and parenchyma by CD8+ and CD4+ T cells. DR15 MS mice uniquely developed spontaneous T cell lesions in brainstem and spinal cord grey matter, and large EAE-inducible lesions in the brain corpus callosum, with relatively low GVHD levels compared to DR15 HI mice. Main limitations of this model for further development are poor monocyte engraftment, lack of demyelination and of lymph node organization and IgG responses. These results show that PBMC humanized mice represent promising experimental tools for MS immunopathology and for testing experimental immunotherapeutics in a patient-specific approach.