title: Elimination of autoreactive B cells in humanized SCID mouse model of SLE.
abstract: Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B-cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well-established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA-specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B-cell activation and proliferation after co-cross-linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human-like system, we used immune-restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re-established after administration of a chimeric molecule consisting of a CR1-specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein-engineered chimera was able to co-cross-link selectively native DNA-specific BCR with the B-cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Nikola S
authors.initials: NS
authors.lastname: Kerekov
authors.forename: Nikolina M
authors.initials: NM
authors.lastname: Mihaylova
authors.forename: Ivan
authors.initials: I
authors.lastname: Grozdev
authors.forename: Todor A
authors.initials: TA
authors.lastname: Todorov
authors.forename: Milena
authors.initials: M
authors.lastname: Nikolova
authors.forename: Marta
authors.initials: M
authors.lastname: Baleva
authors.forename: Maria
authors.initials: M
authors.lastname: Nikolova
authors.forename: Jozsef
authors.initials: J
authors.lastname: Prechl
authors.forename: Anna
authors.initials: A
authors.lastname: Erdei
authors.forename: Andrey I
authors.initials: AI
authors.lastname: Tchorbanov
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology* / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D002460:Cell Line; D002469:Cell Separation; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007167:Immunotherapy / Q000379:methods*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D010455:Peptides; D017463:Receptors, Complement 3b / Q000276:immunology / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001324:Autoantigens; C509991:CR1 protein, human; D010455:Peptides; D017463:Receptors, Complement 3b; D004247:DNA