Peptide-based immunotherapy in a BALB/c mouse model of orally-induced egg allergy

Peptide-based immunotherapy (PIT) represents an attractive approach to develop safe interventions in food allergy, due to its attenuated risk of side-effects. The concept lies in the administration of allergen-derived peptides devoid of IgE-crosslinking activity, but with conserved T-cell determinants in order to maintain immunogenicity. In light of recent reports on the functions of regulatory T cells (Treg), it was hypothesized that T-cell epitope-containing peptides could induce regulatory mechanisms, capable of repressing an allergic response. Using the SPOTS® method, a 12-mer synthetic peptide library spanning the primary sequence of ovalbumin (OVA), a major egg allergen, was constructed and allowed identification of eight B-cell epitope regions. Optimization of an 'ex vivo' splenocyte proliferation assay led to recognition of three immunodominant and one minor T-cell determinants. Five groups of BALB/c mice were orally sensitized to OVA. Groups B, C and D were subsequently administered (s.c.) single synthetic peptides corresponding to OVA immunodominant T cell epitopes, while group E received a cocktail of the three peptides in equal amounts. Groups A and F served as negative (placebo) and positive (no peptide treatment) control groups, respectively. Following the peptide administration, mice were orally challenged with a high dose of OVA. Group B, C and E showed lower serum histamine and specific IgE levels compared to group A, and significantly lower anaphylactic scores were obtained in group E. Group D tended to show higher levels for these same parameters. Real-time RT-PCR analysis of mRNA gene expression in ileum indicated a dominant Th1-response in peptide-treated groups, supported by similar cytokine secretion profiles in splenocyte cultures (ELISA). Importantly, groups C and E were characterized by pronounced mRNA expressions of TGF-[beta] and FOXp3, suggesting the involvement of repressive mechanisms mediated by subsets of Treg cells. The suitability of a PIT approach in a food industrial context was assessed by orally administering egg-white protein hydrolyzates (<=2.0 kDa) to egg-white sensitized-BALB/c mice. The patterns observed were strongly reminiscent of those obtained in allergic mice desensitized to OVA by administration of synthetic peptides. This is the first study to demonstrate the therapeutic potential of PIT in an orally-sensitized mouse model of food allergy.

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