A recombinant TACI-Fc fusion protein targets IgA plasma cells in a mouse model of systemic lupus erythematosus

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 and the factors that increase risk of end organ damage 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 four weeks from the time of disease onset. We focused on female mice treated with BAFF and BAFF/APRIL inhibitors alongside cyclophosphamide as a standard therapy to identify mechanisms associated with improved renal outcomes. Inhibition of BAFF alone had a limited impact on gene expression profiles of diseased mice, decreasing myeloid cell and increasing metabolic gene signatures. However, targeting both BAFF and APRIL through competitive inhibition with a TACI-Fc fusion protein significantly altered immune populations in the spleen and depleted IgA plasma cells and also decreased pro-inflammatory immune cells and cytokines in the kidneys of diseased mice. All therapies had a broad impact on kidney pathology through reduction of proteinuria. Targeting both BAFF and APRIL is necessary to reduce autoreactive plasma cell generation and kidney inflammation effectively and especially to decrease IgA secreting plasma cells. 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.