Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice

Nikolova-Ganeva, Kalina; Gesheva, Vera; Todorov, Todor; Voll, Reinhard; Vassilev, Tchavdar

doi:10.1111/cei.12164

Cited by 6 publications

(7 citation statements)

References 30 publications

(34 reference statements)

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“…Consistent with previous reports [ 7 – 14 ], Bz had a therapeutic effect even in advanced lupus (14-week-old MRL/lpr mice), resulting in marked decreases in serum immunoglobulins and anti-dsDNA antibodies and improved glomerulonephritis. Several groups have reported improved survival rates in Bz-treated NZW/B [ 7 , 9 , 10 , 13 , 14 ] and MRL/lpr [ 7 , 14 ] mice. However, these results for the survival rates were not consistent with the present study.…”

Section: Discussionsupporting

confidence: 92%

“…The reason for this contradiction might be due to the differences in mouse age, disease activity, or just mouse strains. In our study, Bz treatment of MRL/lpr mice was initiated at 14 weeks of age, which is later than in previous reports [ 7 , 14 ], designed to examine the ameliorative and not protective effects of Bz on disease activity, considering the clinical use. Because older (14-week-old) MRL/lpr mice harbor high lpr T cells, which Bz selectively targets (as well as plasma cells), the lethal and toxic effects of Bz may be due to the killing of a large number of lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma cells that synthesize high levels of immunoglobulins have relatively high sensitivity to Bz [ 5 ], which partly explains the clinical success of Bz in treating multiple myeloma [ 6 ]. Bz has been reported to inhibit the production of anti-dsDNA antibody and improve glomerulonephritis, proteinuria, and survival of lupus model mice, such as NZB/W [ 7 – 12 ] and MRL/lpr [ 7 , 13 , 14 ] mice. Recently, Bz treatment has been reported to be effective in treating human SLE [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity

et al. 2017

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1397-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity

et al. 2017

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“…54 Furthermore in SLE animal models bortezomib slows disease onset and ameliorates disease phenotype. 55,56 Although there are no clinical trials in place at present for its use in RA, given the extensive use in malignancy and the emerging potential use in SLE we anticipate that proteasomal inhibitors will be an attractive therapeutic option for RA in the near future.…”

Section: Nuclear Factor Kappa-light Chain Enhancer Of Activated B Celmentioning

confidence: 99%

Emerging immunotherapies for rheumatoid arthritis

Reynolds

Cooles

Isaacs

et al. 2014

Human Vaccines & Immunotherapeutics

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“…13,21 In other studies, bortezomib inhibits the progression of autoimmune diseases, such as systemic lupus erythematosus (SLE), myasthenia gravis and rheumatoid arthritis. [21][22][23][24][25] Here, we speculated that LLPCs participate in the pathogenesis of ITP by consistently secreting anti-platelet autoantibodies, especially in steroid-resistant or relapsed ITP patients. We also hypothesized that bortezomib, as a proteasome inhibitor, can interfere this process by inducing the apoptosis of LLPCs in ITP.…”

Section: Introductionmentioning

confidence: 99%

Proteasome Inhibition with Bortezomib Induces Apoptosis of Long-Lived Plasma Cells in Steroid-Resistant or Relapsed Immune Thrombocytopaenia

Wang

et al. 2018

Thromb Haemost

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Primary immune thrombocytopaenia (ITP) is the most common haemorrhagic disease. Although most patients respond initially to mainstream therapies, such as corticosteroids, immunosuppressants or rituximab, a large proportion of patients fail to respond or relapse. These treatments only affect B lymphocytes or short-lived plasma cells, but not already existing long-lived plasma cells (LLPCs) which persistently secrete antibodies. We hypothesized that LLPCs may play a role in the corticosteroid-resistant or relapsed ITP patients, and bortezomib, a proteasome inhibitor, may act on plasma cells and offer a therapeutic effect. Although a significant difference in the proportion of CD19−CD38hiCD138+ total LLPCs was not observed by flow cytometry, a glycoprotein (GP) IIb/IIIa-specific enzyme-linked immunosorbent spot (ELISpot) assay of sorted CD19−CD138+ LLPCs confirmed the existence of anti-platelet antibody-secreting LLPCs in ITP patients in contrast to healthy controls. Moreover, the LLPCs could be eliminated in the presence of bortezomib by ELISpot assay, which was also confirmed by flow cytometry. Accordingly, a modified monoclonal antibody immobilization of platelet antigen assay of sorted CD19−CD138+ LLPCs revealed that the concentration of anti-platelet antibodies decreased remarkably when cultured with 0.25 ng/mL bortezomib for 5 days. The apoptosis assay demonstrated that bortezomib could induce apoptosis of LLPCs in a concentration-dependent manner. The proteasome activity assay showed that bortezomib significantly reduced the proteasome activity in sorted CD19−CD138+ LLPCs. Furthermore, in active ITP murine models, bortezomib eliminated LLPCs in vivo and alleviated thrombocytopaenia. We conclude that LLPCs participate in the pathogenesis of ITP and bortezomib may have potential as a novel therapeutic regimen.

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Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice

Cited by 6 publications

References 30 publications

Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity

Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity

Emerging immunotherapies for rheumatoid arthritis

Proteasome Inhibition with Bortezomib Induces Apoptosis of Long-Lived Plasma Cells in Steroid-Resistant or Relapsed Immune Thrombocytopaenia

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