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Abstract: The purpose of this study was to evaluate whether a single peptide containing a major T cell epitope might induce peripheral tolerance in a complex allergen model. C57BL/6 mice were sensitized by intraperitoneal injection of house dust mite extract (HDM), and exposed to antigen via trachea instillation. Der p 1 peptide was administered by i.v. before or after sensitization. Lung lavage fluids were analyzed for cellular infiltration. Respiratory exposure of sensitized mice to antigen results in airway inflammation and eosinophilia. Intravenous administration of a single peptide protected sensitized mice from these changes. Further, the emergence of antigen-specific CD25+CD4+ and IL-10 secreting cell populations in DO11.10 mice was demonstrated after peptide administration. Thus, intravenous delivery of a single peptide epitope is capable of inducing peripheral tolerance and protection in a complex allergy model, possibly through regulatory T cells and bystander suppression. [Copyright &y& Elsevier]