Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus

Abstract

B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F1 mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F1 mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4+ T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F1 mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F1 mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.

Activated Renal Macrophages Are Markers of Disease Onset and Disease Remission in Lupus Nephritis

“…The cell surface phenotype of single-cell preparations from perfused kidneys of nephritic mice was compared with that of spleen cells from the same mice using flow cytometry. The spleen cell phenotype of young and nephritic NZB/W mice has previously been described in detail (3,8). Nearly all lymphocyte populations were represented in the kidneys (Table II and Fig.…”

Excessive Production of IFN-γ in Patients with Systemic Lupus Erythematosus and Its Contribution to Induction of B Lymphocyte Stimulator/B Cell-Activating Factor/TNF Ligand Superfamily-13B

“…The extracellular domain of BLyS, which is cleaved by a furin proteinase and released into body fluids such as serum or cerebral spinal fluid, is called soluble BLyS (sBLyS) (21). BLyS transgenic mice developed a lupus-like syndrome (24,26,27), whereas the blockade of the BLyS signal provided a therapeutic benefit to lupus model mice (24,28,29). Increased levels of serum sBLyS (30 -32) as well as BLyS mRNA (31) of peripheral blood leukocytes have been reported in patients with SLE.…”

The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus

“…Constitutive over-expression of BAFF in otherwise non-autoimmune-prone mice often leads to SLE-like features, including elevated circulating titers of multiple autoantibodies, renal immunopathology, and clinical disease [32][33][34]. Conversely, development of disease in SLE-prone mice is greatly attenuated by genetic disruption of the Baff gene [35] or by pharmacologic treatment with a BAFF antagonist [33,[36][37][38].…”