Mucosal Tolerance Induced by an Immunodominant Peptide from Rat α3(IV)NC1 in Established Experimental Autoimmune Glomerulonephritis

Abstract

Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the noncollagenous domain of the ␣ 3 chain of type IV collagen, ␣3(IV)NC1. Recent studies have identified an immunodominant peptide, pCol (24-38), from the N-terminus of rat ␣3(IV)NC1; this peptide contains the major B-and T-cell epitopes in EAG and can induce crescentic nephritis. In this study, we investigated the mechanisms of mucosal tolerance in EAG by examining the effects of the nasal administration of this peptide after the onset of disease. A dose-dependent effect was observed: a dose of 300 g had no effect, a dose of 1000 g resulted in a moderate reduction in EAG severity, and a dose of 3000 g produced a marked reduction in EAG severity accompanied by diminished antigen-specific, T-cell proliferative responses. These results demonstrate that mucosal tolerance in EAG can be induced by nasal administration of an immunodominant peptide from the N-terminus of ␣3(IV)NC1 and should be of value in designing new therapeutic strategies for patients with Goodpasture's disease and other autoimmune disorders.

Anti-Glomerular Basement Membrane Disease

“…Better understanding of T cell functions, and in particular the role of regulatory cells that may suppress disease, may have therapeutic significance, both in anti-GBM disease and other autoimmune conditions. The induction of immunologic tolerance using mucosal administration of GBM antigen has been described in experimental models (96), which may likewise have therapeutic potential. Finally, the inciting events that cause autoimmunity to GBM antigens remain unclear.…”

Antigen Identification in Membranous Nephropathy Moves toward Targeted Monitoring and New Therapy

“…Nasal administration of the recombinant NC1 domain of ␣3 type IV collagen, or an immunodominant peptide thereof, induces tolerance in a model of anti-glomerular basement membrane GN. 38,39 We have identified two immunodominant epitopes on the neutral endopeptidase antigen that are recognized specifically by maternal antibodies. 40 Because future pregnancies in neutral endopeptidase-immunized mothers are high risk for the fetus, 41 epitopedriven therapies, including neutralization of pathogenic antibodies with immunodominant peptides and induction of mucosal tolerance, are needed in addition to nonspecific immunosuppressive therapy.…”

Myeloperoxidase Peptide–Based Nasal Tolerance in Experimental ANCA–Associated GN

“…[10][11][12] The induction of tolerance by mucosal administration of autoantigens or immunodominant/immunogenic peptides has been reported in various experimental models of autoimmune diseases, including encephalomyelitis, 13,14 myasthenia gravis, 15,16 uveitis, 16,17 diabetes, [18][19][20] arthritis, [21][22][23] and autoimmune GN. 24,25 In several of these studies, nasal administration of the immunodominant peptide was more effective in inducing tolerance than oral peptide administration. 22,23,25,26 Despite considerable research in this area, the mechanisms involved in the induction of mucosal tolerance are uncertain.…”