RESUMEN
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.
Asunto(s)
Anticuerpos Antinucleares/inmunología , Anticuerpos Monoclonales/inmunología , Linfocitos B/inmunología , Inmunoterapia/métodos , Lupus Eritematoso Sistémico/inmunología , Animales , Anticuerpos Antinucleares/biosíntesis , Anticuerpos Antinucleares/uso terapéutico , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/uso terapéutico , Autoantígenos/inmunología , Autoinmunidad/inmunología , Western Blotting , Línea Celular , Separación Celular , ADN/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunoprecipitación , Activación de Linfocitos/inmunología , Ratones , Ratones SCID , Péptidos , Receptores de Complemento 3b/inmunología , Receptores de Complemento 3b/uso terapéutico , Transducción de Señal/inmunologíaRESUMEN
The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory FcgammaIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcgammaRIIb antibody. This chimeric antibody was added to cultured spleen cells from sick MRL/lpr mice, immunized with diphtheria toxoid, resulting in reduction of the numbers of anti-DNA but not of anti-diphtheria IgG antibody-producing cells. Intravenous infusions with the DNA-peptide antibody chimera to 7-wk-old animals prevented the appearance of IgG anti-DNA antibodies and of albuminuria in the next 2 months. The administration of the DNA-peptide chimeric antibody to 18 wk-old mice with full-blown disease resulted in the maintenance of a flat level of IgG anti-DNA antibodies and in delay of the aggravation of the lupus glomerulonephritis. The use of chimeric antibodies targeting inhibitory B lymphocyte receptors represents a novel approach for the selective suppression of autoreactive disease-associated B cells in autoimmune diseases.