Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice
Irini Papazian,
Maria Kourouvani,
Anastasia Dagkonaki,
Vasileios Gouzouasis,
Lila Dimitrakopoulou,
Nikolaos Markoglou,
Fotis Badounas,
Theodore Tselios,
Maria Anagnostouli,
Lesley Probert
Affiliations
Irini Papazian
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
Maria Kourouvani
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece; Athens International Master’s Programme in Neurosciences, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
Anastasia Dagkonaki
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece
Vasileios Gouzouasis
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece; Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
Lila Dimitrakopoulou
Department of Hematology, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
Nikolaos Markoglou
Research Immunogenetics Laboratory, Multiple Sclerosis and Demyelinating Diseases Unit, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, NKUA, Aeginition University Hospital, Athens, Greece
Fotis Badounas
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece; Transgenic Technology Unit, Hellenic Pasteur Institute, Athens, Greece
Theodore Tselios
Department of Chemistry, University of Patras, Patras, Greece
Maria Anagnostouli
Research Immunogenetics Laboratory, Multiple Sclerosis and Demyelinating Diseases Unit, First Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, NKUA, Aeginition University Hospital, Athens, Greece
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 (PBMCs) 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 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 gray 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.
