AB0213 Alleviation of nephritis in lupus-prone NZB/WF1 mice by a combination treatment of thalidomide plus prednisolone

Abstract

Background Proliferative lupus nephritis (Class III and IV) is the most severe form of lupus nephritis. The use of intravenous or oral prednisolone (PL) plus either intravenous cyclophosphamide or oral mycophenolate mofetil (MMF) currently is recommended as the standard induction therapy for proliferative lupus nephritis. However, despite improved outcomes with these induction therapies, end-stage renal disease still occurs in up to 30% of patients over a 20-year disease course. Thus, a new therapeutic modality is necessary. Thalidomide is a drug to treat multiple myeloma. Thalidomide can modulate NF-κB activity in myeloma cells, resulting in up-regulating pro-apoptotic regulators and down-regulating anti-apoptotic proteins. Recently, NF-κB was rediscovered to regulate mesangial proliferation in lupus-prone mice. Thus, considering the action-mechanism of thalidomide and its well-established efficacy in multiple myeloma, thalidomide could be an additional treatment for lupus nephritis, comparable to current regimes. Objectives We first investigated the efficacy of thalidomide on nephritis in lupus-prone mice and compared it to mycophenolate mofetil plus prednisolone. Methods Forty-three female NZB/WF1 mice were divided into eight groups (untreated; 1.7, 5, or 10 mg/kg of thalidomide alone; 1.7, 5, or 10 mg/kg of thalidomide plus prednisolone; and mycophenolate mofetilplus prednisolone). Proteinuria and histological damages were evaluated. Immune-complex deposition and nuclear translocation of NF-κB in kidney tissues were assessed by immunofluorescence staining. Serum concentration of anti-ds DNA and immunoglobulin G subclasses were also measured. Results In comparison with untreated mice, mice treated with 5 or 10 mg/kg of thalidomide plus prednisolone, or mycophenolate mofetilplus prednisoloneshowed a significant decrease in proteinuria and significantly lowered glomerular and tubular damage scores. Treatment with either 5 or 10 mg/kg of thalidomide plus prednisolone or mycophenolate mofetil plus prednisolone significantly decreased immune-complex accumulation, reduced the serum concentration of anti-ds-DNA, IgG2a, IgG2b and IgG3, and inhibited nuclear translocation of NF-κB in kidney tissues, compared to no treatment. Conclusions Thalidomide plus PL combination therapy significantly attenuated nephritis in lupus-prone mice. Thalidomide plus PL decreased the serum concentration of anti-ds DNA and IgG subclasses, and reduced glomerular deposition of immune complexes. Also they inhibited nuclear translocation of NF-kB and finally alleviated both proteinuria and histological renal damage. These data suggest that thalidomide plus PL might be anti-inflammatory in lupus nephritis pathophysiology and could serve as an additional therapy for lupus nephritis. Disclosure of Interest None Declared

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

“…Bortezomib and delanzomib have been shown to deplete plasma cells, reduce anti-dsDNA titers, and alleviate renal disease in the NZB/W F1 and MRL/lpr mice [119][120][121]. Treatment of the lupus-prone mice with carfilzomib, bortezomib, or the immunoproteasome-specific inhibitors such as ONX0914 prevented disease progression and abrogated glomerulonephritis, along with a reduction in autoantibody levels and production of IFNα by TLR-activated pDCs in vitro and in vivo [122].…”