Selective silencing of DNA-specific B lymphocytes delays lupus activity in MRL/lpr mice

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...

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Bibliographic Details
Published in:European journal of immunology 2007-12, Vol.37 (12), p.3587-3596
Main Authors: Tchorbanov, Andrey I, Voynova, Elisaveta N, Mihaylova, Nikolina M, Todorov, Todor A, Nikolova, Maria, Yomtova, Vihra M, Chiang, Bor-Luen, Vassilev, Tchavdar L
Format: Article
Language:English
Subjects:
Animals
Antibodies, Antinuclear - biosynthesis
Antibodies, Antinuclear - immunology
Antibodies, Monoclonal - therapeutic use
Antibody Specificity
Apoptosis - drug effects
Autoreactive B cells
B-Lymphocyte Subsets - drug effects
B-Lymphocyte Subsets - immunology
Cells, Cultured - immunology
Cross-Linking Reagents - pharmacology
Cross-Linking Reagents - therapeutic use
Diphtheria Toxoid - immunology
Disease Models, Animal
DNA - immunology
FcγIIb receptor
Female
Immunoconjugates - therapeutic use
Immunoglobulin G - biosynthesis
Immunoglobulin G - blood
Immunoglobulin G - immunology
Immunosuppressive Agents - therapeutic use
Lupus Erythematosus, Systemic - genetics
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - prevention & control
Lupus Erythematosus, Systemic - therapy
Mice
Mice, Inbred MRL lpr
Molecular Mimicry
Oligopeptides - administration & dosage
Oligopeptides - chemical synthesis
Oligopeptides - immunology
Oligopeptides - therapeutic use
Receptors, Antigen, B-Cell - drug effects
Receptors, Antigen, B-Cell - immunology
Receptors, IgG - drug effects
Receptors, IgG - immunology
Recombinant Fusion Proteins - administration & dosage
Recombinant Fusion Proteins - therapeutic use
Systemic lupus erythematosus
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Summary: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 FcγIIb surface receptors. A hybrid molecule was constructed by coupling the DNA-mimicking DWEYSVWLSN peptide to a monoclonal anti-mouse FcγRIIb 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.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200737143