Abstract
BackgroundBortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity.MethodsFemale MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 μg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice.ResultsThe anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice.ConclusionsIn spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.
Highlights
Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells
We demonstrated that immunological activity was higher in 14-week-old than 10-week-old MRL/lpr mice, that Bz treatment was associated with a higher mortality rate in 14-week-old than in 10-week-old MRL/lpr mice, and that, in spite of its therapeutic effects on antibody production, Bz treatment causes significantly elevated serum levels of IL-6 and Tumor necrosis factor alpha (TNF-α) in 14-week-old MRL/lpr mice
Serological analysis revealed that serum levels of IgG1, IgG2a, IgG3, and anti-dsDNA antibody were significantly higher in the 14-week-old than in the 10-week-old mice
Summary
Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). One therapeutic approach is to diminish the production of pathogenic antibodies Toward this goal, several experimental therapeutic strategies have targeted molecules involved in pathways that control B-cell activation into plasma cells [2, 3]. Our group was the first to report a randomized control study on the effects of Bz in patients with active lupus [17]. In order to safely use Bz to treat patients with refractory SLE, we need to clarify its mechanisms of toxicity in order to devise preventive strategies to mitigate its adverse effects
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