Selective silencing of disease-associated B-lymphocytes by chimeric molecules targeting their Fc gamma IIb receptor.
The presently used approaches to silence autoreactive disease-associated B cells act indiscriminately and more specific therapies are obviously needed. In the present study, we analyze the ability of a chimeric antibody to suppress selectively pathological autoreactive B-lymphocytes in lupus-prone mice by cross-linking their surface Ig receptors with the inhibitory IgG Fc gamma RIIb receptors. The chimera was constructed by coupling an immunodominant mouse Histone 1 peptide to a rat monoclonal anti-mouse CD32 (Fc gamma RIIb) antibody. The administration of these chimeric molecules to MRL/lpr mice with initial and with full-blown disease resulted in the reduction of the levels of IgG anti-Histone 1 antibodies, of the albuminuria levels, of the size of lymphoid organs and in prevention of the development of skin lesions. The observed effect was limited to lupus-associated B cells only, as the treatment did not decrease the IgG antibody response to an administered foreign antigen. This study demonstrates the possibility to silence selectively autoreactive B cells and to delay the progression of an autoimmune disease using chimeric antibody molecules.
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood*; D001402:B-Lymphocytes / Q000187:drug effects*; D005260:Female; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; C080571:Fc gamma receptor IIB; D006657:Histones; D010455:Peptides; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins