Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus.
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.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Meera
M
Ramanujam
Xiaobo
X
Wang
Weiqing
W
Huang
Lena
L
Schiffer
Christine
C
Grimaldi
Alla
A
Akkerman
Betty
B
Diamond
Michael P
MP
Madaio
Anne
A
Davidson
D000069594:Abatacept; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D002352:Carrier Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D053264:B-Cell Activating Factor; C490314:Caml protein, mouse; D002352:Carrier Proteins; D018796:Immunoconjugates; D007136:Immunoglobulins; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C486361:Tnfrsf13b protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept