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

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2004; 173(5):3524-34. DOI: 10.4049/jimmunol.173.5.3524
Source: PubMed

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.

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Available from: Anne Davidson, Sep 27, 2015
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    • "In experiments using immunization with conventional antigens, survival of murine memory B cells in vivo and of human memory B cells in vitro [38] was found to be independent of BAFF and APRIL signaling [16,30,31]. Whether there is any influence of BAFF or APRIL on selection or expansion of autoreactive memory B cells is not known. "
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    ABSTRACT: B-cell activating factor (BAFF), a member of the family of TNF-like cytokines, supports the survival and differentiation of B cells. The successful development of belimumab, a human antibody targeting soluble BAFF, has marked an important milestone in the development of biologic therapy for treatment of systemic lupus erythematosus (SLE), although much remains unknown regarding the clinical utility of BAFF inhibition in SLE and other autoimmune diseases. In the present review, we provide an overview of the knowledge concerning BAFF's role in murine and human B-cell development and maturation, as well as the clinical and mechanistic effects of BAFF inhibition in human SLE.
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    • "In the SLE patients, it is reported that the clinical use of glucocorticoid or other immunosuppressants, multiple antibiotics and steroidinduced diabetes always contributed to the dysfunction of immune response . And the dysfunction of immune cells including T cell, B cell and dendritic cell was demonstrated to promote SLE patients more susceptible for the occurrence of IFI (Nambiar et al., 2002; Nevzorova et al., 2006; Ramanujam et al., 2004; Reefman et al., 2007; Seta et al., 2002; Takeuchi, 2002; Traustadottir et al., 2002). Therefore, it is believed that the imbalancement of immune response of host be capable of increasing the risk for the incidence of IFI (Petri and Genovese, 1992). "
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    • "This is consistent with the lack of decrease for plasmablasts/PC in APRIL−/− compared to control mice. The increased survival observed here is very similar to the APRIL/BAFF antagonism mediated with soluble TACI during treatment and at early time points after treatment stop (6 weeks) [10], [11], [12]. In this time frame, it is also very similar to the BAFF-R treatment [10], [11], [13], [14]. "
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    ABSTRACT: SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily mediating antibody-producing plasma cell (PC)-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T-cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used.
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