Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus

Meera Ramanujam, Xiaobo Wang, Weiqing Huang, Lena Schiffer, Christine Grimaldi, Alla Akkerman, Betty Diamond, Michael P. Madaio, Anne Davidson

Research output: Contribution to journalArticle

110 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3524-3534
Number of pages11
JournalJournal of Immunology
Volume173
Issue number5
DOIs
StatePublished - Sep 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ramanujam, M., Wang, X., Huang, W., Schiffer, L., Grimaldi, C., Akkerman, A., Diamond, B., Madaio, M. P., & Davidson, A. (2004). Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. Journal of Immunology, 173(5), 3524-3534. https://doi.org/10.4049/jimmunol.173.5.3524