RESUMO
A novel approach for the selective silencing of targeted autoreactive B lymphocytes is reviewed that mimics the physiological mechanisms for suppressing B cell activity. It is based on the use of bi- or tri-specific chimeric antibodies that cross-link BCRs with a pre-selected antigen-binding specificity with one or more inhibitory types of receptors on the surface of the same disease-associated B lymphocyte. The effect of these engineered antibodies was proved to be specific as they only suppressed the production of the targeted pathological antibodies while sparing those with other specificities. The administration of the chimeric molecules to lupus-prone MRL/lpr mice resulted in decreased levels of disease-associated IgG autoantibodies and of proteinuria, in the prevention of cutaneous lesions, in decreased sizes of the lymphoid organs and in prolonged survival. These results prove that it is indeed possible to selectively silence unwanted B lymphocytes as well as to significantly delay the natural course of a spontaneous antibody-mediated autoimmune disease.
Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Autoimunidade , Linfócitos B/imunologia , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Autoanticorpos , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/patologia , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos , Camundongos Endogâmicos MRL lpr , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de IgG/imunologia , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologiaRESUMO
Intravenous immunoglobulin (IVIg) preparations are known to modulate autoimmune/inflammatory diseases through several F(ab')(2)- and Fc-dependent mechanisms. In this study, we show that the in vitro and the in vivo exposure of B lymphocytes from lupus-prone and from healthy mice to IVIg results in an increased expression of their surface inhibitory FcgammaIIB receptors. Further, this exposure enhanced the ability of a chimeric antibody, cross-linking FcgammaRIIB and immunoglobulin receptors on DNA-specific B lymphocytes, to suppress IgG anti-DNA antibody production. F(ab')(2) fragments of IVIg had a similar activity as the intact preparation, whereas Fc fragments had no effect. This study describes a novel approach with clinical relevance for modulating B lymphocyte activity.
