T cell targeted strategies for improved efficacy and safety of specific immunotherapy for allergic disease.

Allergic diseases including asthma, rhinitis and eczema are known to be a major health and economic burden worldwide. Specific immunotherapy (SIT) is potentially curative but restricted in use, e.g. for asthmatics, due to risk of serious adverse events. Safer, effective SIT preparations require elucidation of mechanisms and immunoregulatory factors. Allergen-specific T cells play a pivotal role. For allergic individuals, allergen-stimulated T cells largely secrete IL-4, IL-5 and IL-13 (Th2-type cytokines), whereas non-allergics show predominant IFN-γ secretion (Th1-type). Clinically successful SIT is accompanied by altered allergen-specific T cell response, with decreased Th2/Th1 ratio, enhanced IL-10 secretion and regulatory T cell induction. Contributing factors include allergen concentration and form, adjuvant and antigen presenting cell type. In conventional SIT, high dose unfractionated allergen extracts are injected incrementally via the subcutaneous route. To avoid adverse IgE-mediated events but retain efficacy, hypoallergenic T cell-reactive allergen derivatives can be used. These include peptides containing dominant T cell epitopes of allergens, chemically-modified allergens, and recombinant whole or mutant allergens. Such approaches have been evaluated successfully in animal models and early phase clinical trials. Adjuvants and carriers including bacterial and viral components, liposomes and DNA vaccines also promote repolarisation of T cell response and regulatory T cell induction. However caution is needed as excessive IFN- γ secretion may invoke pathogenic inflammation. Sublingual administration has fewer adverse events and is gaining popularity for respiratory allergens, and other routes including intranasal and oral are under evaluation. T cell targeted strategies will facilitate wider clinical application of SIT and reliable laboratory assays for monitoring treatment.