Utility of Altered Peptide Ligands to Protect against Allergic Asthma

Allergic asthma is a prevailing disease worldwide. It is triggered by allergen, characterized by Th2 responses with airway inflammation and serum IgE elevation, and leading to airway obstruction. Immunotherapy with specific allergens has been shown to be effective in IgE-mediated diseases. The clinical application of immunotherapy with naive allergen is offset by the risk of causing severe IgE-mediated systemic reactions and occasionally anaphylactic shock. In the last decade, the discovery of regulatory T cells capable of inhibiting Th2 cells has rekindled the interest of immunotherapy to protect against asthma. It would be a good strategy to develop tolerogenic vaccines that generate regulatory T cells in vivo without the unwanted side effect, thereby eliminating the risk of anaphylaxis. One of the approaches would be by the use of altered peptide ligands. We hypothesize that sustained suboptimal antigenic stimulation can induce antigen-specific adaptive regulatory T cells in the periphery. Certain superagonists might lead to the deletion of pathogenic T cells and reverse airway inflammation without the cytokine storm. In this project, we plan to develop tolerogenic vaccines with altered peptide ligands to protect against asthma. Our preliminary data showed that one of altered peptide ligands we designed could significantly inhibit airway hyper-reactivity, reduce eosinophilia and the production of antigen-specific IgE in an animal model. Adoptive transfers of tolerant T cells were able to reduce airway hyperreactivity and to reverse airway inflammation. By using this model, we will study the developmental biology of adaptive regulatory T cells and dissect the role of natural regulatory T cell and adaptive regulatory T cells in the immunological tolerance. We wish to study the mode of action mediated by the adaptive regulatory T cells and the role of CCR 5 in the homing of regulatory T cells. Finally, we will test the potential of superagonists in the deletion of pathogenic T cells and to reverse airway inflammation. This project might lead to significant advances on our understanding in T cell tolerance and to pave an avenue for tolerogenic vaccines to the clinical trial.

Project ID:PC9902-1696 
External Project ID:NSC98-2320-B182-024-MY3