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-orga n-specific autoimmune disorder. Immune complex-mediated kidney disease is t he major cause of mortality. Apoptotic cells in the epidermis are a possibl e source of self Ags, and apoptosis of endothelial cells and lymphocytes is thought to contribute to end-organ damage. We have previously shown that f emale transgenic mice expressing IFN-gamma in the epidermis develop inflamm atory skin disease and features of SLE that have striking parallels with th e human condition. We have now tested the effects of a pan-caspase inhibito r, carbobenzoxy-valyl-alanyl-aspartyl-(beta -o-methyl)-fluoromethylketone, on disease progression. Daffy s.c. administration of carbobenzoxy-valyl-ala nyl-aspartyl(beta -o-methyl)-fluoromethylketone to female transgenic mice o ver a 3-wk period resulted in significant amelioration of both glomerular a nd interstitial renal damage, independent of the effects on autoantibody le vels or skin inflammation. We propose that apoptosis inhibitors could be be neficial in the treatment of human SLE.