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 F(1) 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 F(1) 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 F(1) 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 F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.
Highlights
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The studies presented in this report have confirmed that a short course of the murine BAFF and A proliferation-inducing ligand (APRIL) inhibitor transmembrane activator and calcium modulator ligand interactor (TACI)-Ig, given as a single dose of adenovirus, has a profound effect on disease onset in NZB/W F1 mice
We showed that the addition of a 2-wk course of CTLA4-Ig prolonged the duration of TACI-Ig expression and the nephritis-free survival of the mice; this combination had beneficial effects in older mice with established disease
Summary
BAFF, B cell-activating factor belonging to the TNF family; TACI, transmembrane activator and calcium modulator ligand interactor; BCMA, B cell maturation Ag; APRIL, A proliferation-inducing ligand; Ad-L, LacZ adenovirus; Ad-L/C, LacZ adenovirus and CTLA4-Ig; Ad-T, TACI-Ig adenovirus; Ad-T/C, TACI-Ig adenovirus and CTLA4-Ig; AID, activation-induced cytidine deaminase; MZ, marginal zone; Ox, oxazolone; SLE, systemic lupus erythematosus; T1, transitional type 1; T2, transitional type 2. Overexpression of BAFF has been observed in spontaneous murine systemic lupus erythematosus (SLE) models and in humans with autoimmune diseases [13, 14]. These findings have suggested that antagonism of BAFF may be a useful therapeutic approach for autoimmune disease. Antagonism of BAFF can be achieved by administration of a soluble form of any of the three BAFF receptors Both TACI-Ig and BAFF-R-Ig have been reported to delay the onset of SLE in the murine NZB/W F1 model [2, 15]. A short course of TACI-Ig and CTLA4-Ig can reverse nephritis and prolong survival even in older mice, suggesting that B cell depletion may be an effective therapeutic strategy for active SLE
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