B-cell targeted therapy is effective for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis(RA),although there are setbacks in RA clinical trials.In this study,we designed a novel B-cell...B-cell targeted therapy is effective for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis(RA),although there are setbacks in RA clinical trials.In this study,we designed a novel B-cell activating factor(BAFF)antagonist:BAFF-Trap,a recombinant glycoprotein with BAFF-binding domains of two BAFF receptors(TACI and Br3)linked to Fc domain of human IgG1.Unlike TACI-Fc,BAFF-Trap bound BAFF but not APRIL(a proliferation-inducing ligand),and significantly suppressed the development of collagen-induced arthritis and adjuvant-induced arthritis.Furthermore,BAFF-Trap inhibited proinflammatory cytokine expression,ameliorated joint damage and suppressed B-and T-cell activation.BAFF-Trap reduced dendritic cells in joints,and increased regulatory T cell,regulatory B-cell,and M2 macrophage.The function of BAFF-Trap was related to inhibition of canonical and noncanonical NF-κB activation.Thus,BAFF-Trap may be a valuable agent for the effective treatment of RA.展开更多
基金This study was supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2012ZX09103301-025,No.2018ZX09201018-013,and No.2018ZX09733001)China Postdoctoral Science Foundation(No.2018M633370).
文摘B-cell targeted therapy is effective for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis(RA),although there are setbacks in RA clinical trials.In this study,we designed a novel B-cell activating factor(BAFF)antagonist:BAFF-Trap,a recombinant glycoprotein with BAFF-binding domains of two BAFF receptors(TACI and Br3)linked to Fc domain of human IgG1.Unlike TACI-Fc,BAFF-Trap bound BAFF but not APRIL(a proliferation-inducing ligand),and significantly suppressed the development of collagen-induced arthritis and adjuvant-induced arthritis.Furthermore,BAFF-Trap inhibited proinflammatory cytokine expression,ameliorated joint damage and suppressed B-and T-cell activation.BAFF-Trap reduced dendritic cells in joints,and increased regulatory T cell,regulatory B-cell,and M2 macrophage.The function of BAFF-Trap was related to inhibition of canonical and noncanonical NF-κB activation.Thus,BAFF-Trap may be a valuable agent for the effective treatment of RA.
