title: 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.
  
  
  CONCLUSIONS
  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 ANCA-associated renovascular disorders.
authors.affiliation: Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Saiga
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tokunaka
authors.forename: Eiji
authors.initials: E
authors.lastname: Ichimura
authors.forename: Eriko
authors.initials: E
authors.lastname: Toyoda
authors.forename: Fuminori
authors.initials: F
authors.lastname: Abe
authors.forename: Minako
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
authors.forename: Masao
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D006417:Hematuria / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000502:physiology; D008206:Lymphatic Diseases / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D011507:Proteinuria / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D011743:Pyrimidines / Q000494:pharmacology*; D015996:Survival Rate; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C509974:(S)-1-(5-hydroxy-1,5-dimethylhexyl)-3-(7-(4-methoxyphenyl)-(1,2,4-triazolo(1,5-a)pyrimidin-2-yl))urea; D019268:Antibodies, Antineutrophil Cytoplasmic; D016207:Cytokines; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles