NK026680, a novel suppressant of dendritic cell function, prevents the development of rapidly progressive glomerulonephritis and perinuclear antineutrophil cytoplasmic antibody in SCG/Kj mice

Abstract

Objective. NK026680 is a newly identified type of immunosuppressive agent that inhibits dendritic cell (DC) functions and consequently reduces the mortality of mice with experimental acute graft-versus-host disease. This study was undertaken to evaluate NK026680 suppression of DC functions in preventing development of rapidly progressive glomerulonephritis (RPGN) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) in SCG/Kj mice.Methods. Oral administration of NK026680 to SCG/Kj mice began when mice were 8-10 weeks old, before the onset of disease, and continued for 56 days. The efficacy of NK026680 was evaluated using the mortality of mice, the results of urinalysis, histopathologic evaluation for glomerular injury, and immunofluorescence staining for the detection of immune complex (IC) deposition in glomeruli, and by assessing lymphadenopathy and measuring autoantibody titers.Results. Oral administration of NK026680 at a dosage of 25 mg/kg once daily or 50 mg/kg once daily significantly suppressed 1) spontaneous mortality, 2) proteinuria and hematuria, 3) blood urea nitrogen levels, 4) glomerular damage characterized histopathologically, 5) IC deposition in glomeruli, 6) the development of pANCA and anti-DNA antibodies, and 7) lymphadenopathy. Conclusion. The newly identified DC inhibitor, NK026680, prevented the onset of RPGN, autoantibody production, and lymphadenopathy in SCG/Kj mice, suggesting a crucial role for DC function in these autoimmune phenotypes. NK026680 may be a potent immunosuppressive agent for the treatment of ANCAassociated renovascular disorders.Dendritic cells (DCs) play a central role in initiating and regulating immune responses through antigen presentation (signal 1), costimulatory signals (signal 2), and soluble factors (1,2). Several studies have demonstrated that blockade of the costimulatory signal from DCs markedly suppresses autoimmune diseases (3) and, conversely, that the prolonged presentation of self antigens by DCs exacerbates autoimmune diseases in animal models (4-7). These findings confirm the pathologic role of DCs in the pathogenesis of autoimmune diseases, suggesting that DC function is a potential target for autoimmune therapy. We therefore attempted to develop a pharmacologic approach to suppressing DC functions in vivo.Recently, we succeeded in isolating a new type of immunosuppressive agent, NK026680, by screening a large number of synthetic compounds.

Correlation of interleukin‐6 and monocyte chemotactic protein‐1 concentrations with crescent formation and myeloperoxidase‐specific anti‐neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti‐interleukin‐6 receptor antibody or mizoribine

“…In addition to IL‐6 and MCP‐1, we found that serum concentrations of several cytokines and chemokines such as IL‐4, IL‐10, IL‐12p40, G‐CSF, GM‐CSF, IFN‐γ, and RANTES are significantly increased with aging in SCG/Kj mice. We have previously shown that concentrations of IL‐10 and IL‐12p40 are decreased by treatment with 15‐deoxyspergualin , further indicating that these two cytokines are important in the development of RPGN and would be potential therapeutic targets.…”

Dendritic cells and macrophages in the kidney: a spectrum of good and evil

“…Creation of NZB mice lacking IRF8 (and thus lacking pDC) or mice carrying a mutation of the peptide-histone transporter solute carrier family 15, member 4 (SLC154, that retain pDC incapable of producing type I IFN) demonstrate amelioration of lupus pathology, implicating pDC in lupus pathogenesis 118. In perinuclear anti-neutrophil cytoplasmic Ab (pANCA) positive SCG/Kj mice119, a novel triazolopyrimidine derivative (NK026680) that inhibits DC function suppresses multiple disease manifestations and Ab development120.…”

Review article: Kidney dendritic cells: Their role in homeostasis, inflammation and transplantation

“…Suppression of DC function can prevent onset of rapidly progressive glomerulonephritis (RPGN) 59 . Saiga et al.…”