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Inducing Tolerance by Intranasal Administration of Long Peptides in Naive and Primed CBA/J Mice¹

Mireille Astori^*,, Christophe von Garnier^*, Alexander Kettner, Nathalie Dufour^*, Giampietro Corradin and François Spertini^2,*

^* Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland

To assess the capacity of a peptide-based immunotherapy to induce systemic tolerance via the nasal route, we designed three long overlapping peptides of 44–60 aa covering the entire sequence of phospholipase A₂ (PLA₂), a major bee venom allergen. Both prophylactic and therapeutic intranasal administrations of long peptides to PLA₂-hypersensitive CBA/J mice induced specific T cell tolerance to the native allergen. In prophylactic conditions, this tolerance was marked by a suppression of subsequent specific IgE response, whereas the therapeutic approach in presensitized mice induced a more than 60% decrease in PLA₂-specific IgE. This decline was associated with a shift in the cytokine response toward a Th1 profile, as demonstrated by decreased PLA₂-specific IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN- ratios. T cell transfer from long peptide-tolerized mice to naive animals abrogated the expected anti-PLA₂ IgE and IgG1 Ab response, as well as specific T cell proliferation, but enhanced specific IgG2a response upon sensitization with PLA₂. These events were strongly suggestive of a clonal anergy affecting more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate that allergen-derived long peptides delivered via the nasal mucosa may offer an alternative to immunotherapy with native allergens without the inherent risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast to immunotherapy strategies based on short peptides, have the advantage of covering all potential T cell epitopes, and may represent novel and safe tools for the therapy of allergic diseases.

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