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 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.
Tchorbanov
Andrey I
AI
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Voynova
Elisaveta N
EN
Mihaylova
Nikolina M
NM
Todorov
Todor A
TA
Nikolova
Maria
M
Yomtova
Vihra M
VM
Chiang
Bor-Luen
BL
Vassilev
Tchavdar L
TL
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology; D003432:Cross-Linking Reagents / Q000494:pharmacology / Q000627:therapeutic use*; D004247:DNA / Q000276:immunology; D004168:Diphtheria Toxoid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects* / Q000276:immunology; D017452:Receptors, IgG / Q000187:drug effects* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D004168:Diphtheria Toxoid; C499172:Fcgr2b protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C526794:aspartyl-tryptophyl-glutamyl-tyrosyl-seryl-valyl-tryptophyl-leucyl-seryl-asparagine; D004247:DNA