Cutting edge: amelioration of kidney disease in a transgenic mouse model of lupus nephritis by administration of the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(beta-o-methyl)-fluoromethylketone.
Systemic lupus erythematosus (SLE) is a common, potentially fatal, non-organ-specific autoimmune disorder. Immune complex-mediated kidney disease is the major cause of mortality. Apoptotic cells in the epidermis are a possible source of self Ags, and apoptosis of endothelial cells and lymphocytes is thought to contribute to end-organ damage. We have previously shown that female transgenic mice expressing IFN-gamma in the epidermis develop inflammatory skin disease and features of SLE that have striking parallels with the human condition. We have now tested the effects of a pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-(beta-o-methyl)-fluoromethylketone, on disease progression. Daily s.c. administration of carbobenzoxy-valyl-alanyl-aspartyl-(beta-o-methyl)-fluoromethylketone to female transgenic mice over a 3-wk period resulted in significant amelioration of both glomerular and interstitial renal damage, independent of the effects on autoantibody levels or skin inflammation. We propose that apoptosis inhibitors could be beneficial in the treatment of human SLE.
Seery
J P
JP
Keratinocyte Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
Cattell
V
V
Watt
F M
FM
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006657:Histones / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D012867:Skin / Q000473:pathology
D000590:Amino Acid Chloromethyl Ketones; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006657:Histones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D007371:Interferon-gamma