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

Author:

Papazian Irini1,Kourouvani Maria12,Dagkonaki Anastasia1,Gouzouasis Vasileios13,Dimitrakopoulou Lila4,Markoglou Nikolaos5,Badounas Fotis16,Tselios Theodore7,Anagnostouli Maria5,Probert Lesley1ORCID

Affiliation:

1. Laboratory of Molecular Genetics, Hellenic Pasteur Institute

2. Athens International Master’s Programme in Neurosciences, Department of Biology, National and Kapodistrian University of Athens

3. Department of Molecular Biology and Genetics, Democritus University of Thrace

4. Department of Hematology, Laiko General Hospital, National and Kapodistrian University of Athens

5. 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

6. Transgenic Technology Unit, Hellenic Pasteur Institute

7. Department of Chemistry, University of Patras

Abstract

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.

Funder

Hellenic Ministry of Development and Investment

Publisher

eLife Sciences Publications, Ltd

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