Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. Journal of immunology (Baltimore, Md. : 1950) [J Immunol] Journal article | | Title | Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. | | Author(s) | Ramanujam M, Wang X, Huang W, Schiffer L, Grimaldi C, Akkerman A, Diamond B, Madaio MP, Davidson A | | Institution | Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. | | Source | J Immunol 2004 Sep 1; 173(5):3524-34. | | MeSH | Adaptor Proteins, Signal Transducing
Animals
Autoimmunity
B-Lymphocytes
Carrier Proteins
Disease Models, Animal
Immunoconjugates
Immunoglobulins
Lupus Erythematosus, Systemic
Membrane Proteins
Mice
Phenotype
Receptors, Tumor Necrosis Factor
Recombinant Fusion Proteins
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Tumor Necrosis Factor-alpha
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 15322217 |
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