Dual BAFF and APRIL inhibition with TACI-Fc depletes IgA plasma cells and ameliorates lupus nephritis

B cell activating factor (BAFF) and APRIL play an important role in driving systemic lupus erythematosus (SLE) immunopathogenesis and kidney damage in lupus nephritis (LN); however, the underlying immune mechanisms contributing to disease pathology are poorly understood. To investigate molecular profiles during the progression of LN, we carried out gene expression analysis on kidneys and spleens from lupus-prone NZM2328 mice treated for 4 weeks from the time of disease onset with BAFF and BAFF/APRIL inhibitors. Inhibition of BAFF alone had a limited impact on gene expression profiles of diseased mice. However, targeting both BAFF and APRIL through competitive inhibition with a transmembrane activator and CAML interactor (TACI)-Fc fusion protein significantly altered immune populations in the spleen, depleted IgA plasma cells, and also decreased inflammation in the kidneys of diseased mice. The impact of targeting both members of the BAFF family of cytokines in lupus-prone NZM2328 mice provides support for its application in the treatment of human LN.