Nasal administration of recombinant rat alpha3(IV)NC1 prevents the development of experimental autoimmune glomerulonephritis in the WKY rat

Abstract

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by immunization with either collagenase-solubilized rat glomerular basement membrane (GBM) or the recombinant NC1 domain of the alpha3 chain of type IV collagen [alpha3(IV)NC1]. EAG is characterized by circulating and deposited anti-glomerular basement membrane antibodies, focal necrotizing glomerulonephritis with crescent formation, and glomerular infiltration by T cells and macrophages. Previous studies have demonstrated that oral administration of collagenase-solubilized GBM to WKY rats prevented the development of EAG. Nasal administration of specific autoantigens has been reported to be more effective than oral administration in other models of autoimmune disease. The main aim of this study was to investigate further the concept of mucosal tolerance in EAG by examining the effect of nasal administration of recombinant rat alpha3(IV)NC1. Groups of WKY rats with EAG, induced by immunization with recombinant rat alpha3(IV)NC1, were given alpha3(IV)NC1 nasally on 3 consecutive days before immunization, at total cumulative doses of 25, 100, or 250 microg per rat. A dose-dependent effect was observed on the development of EAG. A dose of 25 microg had no effect on disease; 100 microg resulted in a moderate reduction in the severity of nephritis; and 250 microg led to a marked reduction in circulating and deposited antibodies, albuminuria, severity of glomerular abnormalities, and numbers of glomerular CD8+ T cells and macrophages. In addition, there was a reduction in the proliferative response of splenocytes from rats in the high dose group (250 microg) to alpha3(IV)NC1 in vitro. The results from this study clearly demonstrate for the first time that mucosal tolerance in EAG can be induced by nasal administration of recombinant rat alpha3(IV)NC1 and that this approach is effective in the prevention of crescentic glomerulonephritis. Further work using new antigen-specific treatment strategies may provide a novel approach to the treatment of patients with anti-glomerular basement membrane disease.