When testing with sera of allergic animals, the allergenicity of OVA proteins was enhanced if tyrosine residues were nitrated. Murine IgE antibodies specifically interacted with nOVA leading to an elevation of mediator release if immunizations were performed via the oral route. However, when animals received the OVA preparations systemically via ip. injections, an additional cross-recognition of an unrelated nitrated allergen was observed even if the animals were sensitized with OVA or snOVA. The results of the SGF experiments indicate that nitration of tyrosine residues interferes with the protein stability in the presence of gastric digestive enzymes. The acidic gastric milieu has been discussed to play an important role in nitration as nitrous acid was found to be formed exclusively at low pH, having then the ability to nitrate tyrosine residues of ingested proteins. Nitrated proteins were demonstrated to be cleaved by the pancreatic enzyme chymotrypsin at a significantly slower rate than untreated peptides. After 4 hours of chymotrypsin digestion, 40% of nitrated peptides remained stable compared to 10% of untreated peptides. To our knowledge this is the first report describing that nitration enhances the digestibility of food proteins by gastric enzymes. Pepsin is known to cleave proteins preferentially at phenylalanine, tyrosine and leucine residues. Due to conformational changes upon nitration of tyrosine residues, amino acids interacting with pepsin might become accessible leading to an enhanced susceptibility to gastric, digestive proteases and a reduced immunogenicity if administered via the oral route. However, we have repeatedly demonstrated that our oral immunization protocol of protein feeding under concomitant acid suppression results in allergic sensitization indicated by specific IgE antibodies, leading to the development of food allergy even if food proteins were easily degraded by gastric enzymes. Thus, it might be of special interest that the most efficiently nitrated tyrosine residue within the nOVA protein is part of human as well as murine IgE epitopes of ovalbumin and is also found in a human ovalbumin T cell epitope. Using different MK-1775 routes of allergen application in BALB/c mice, ovalbumin epitopes were analyzed by induced antibodies revealing the tyrosine residue Y107 to be part of an ovalbumin epitope recognized exclusively after oral sensitization. This might offer an explanation why additionally to reduced IgE levels no IgG1 or IgG2a formation was observed after oral immunizations with nOVA. Our data demonstrate that nitration of OVA, as it might occur endogenously e.g. during inflammatory processes, results in reduced de novo sensitization capacity of this common egg.