NK026680, a novel suppressant of dendritic cell function, prevents the development of rapidly progressive glomerulonephritis and perinuclear antineutrophil cytoplasmic antibody in SCG/Kj mice.
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.
Saiga
Kan
K
Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
Tokunaka
Kazuhiro
K
Ichimura
Eiji
E
Toyoda
Eriko
E
Abe
Fuminori
F
Yoshida
Minako
M
Furukawa
Hiroshi
H
Nose
Masato
M
Ono
Masao
M
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*
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