T Cell Targeted Strategies for Improved Efficacy and Safety of Specific Immunotherapy for Allergic Disease
Jennifer M. Rolland, Sara Prickett, Leanne M. Gardner and Robyn E. O’Hehir
Affiliation: Department of Immunology, AMREP, Monash University, Commercial Road, Melbourne, VIC. 3004. Australia.
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.
Keywords: Adjuvant, allergen, antigen presenting cell, DNA vaccine, immunotherapy, mutant allergen, regulatory T cell,
T cell epitope peptide.
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