Immunoregulatory T cell epitope peptides: the new frontier in allergy therapy

Abstract

Allergen immunotherapy (AIT) has been practised since 1911 and remains the only therapy proven to modify the natural history of allergic diseases. Although efficacious in carefully selected individuals, the currently licensed whole allergen extracts retain the risk of IgE-mediated adverse events, including anaphylaxis and occasionally death. This together with the need for prolonged treatment regimens results in poor patient adherence. The central role of the T cell in orchestrating the immune response to allergen informs the choice of T cell targeted therapies for down-regulation of aberrant allergic responses. Carefully mapped short synthetic peptides that contain the dominant T cell epitopes of major allergens and bind to a diverse array of HLA class II alleles, can be delivered intradermally into non-inflamed skin to induce sustained clinical and immunological tolerance. The short peptides from allergenic proteins are unable to cross-link IgE and possess minimal inflammatory potential. Systematic progress has been made from in vitro human models of allergen T cell epitope-based peptide anergy in the early 1990s, through proof-of-concept murine allergy models and early human trials with longer peptides, to the current randomized, double-blind, placebo-controlled clinical trials with the potential new class of synthetic short immune-regulatory T cell epitope peptide therapies. Sustained efficacy with few adverse events is being reported for cat, house dust mite and grass pollen allergy after only a short course of treatment. Underlying immunological mechanisms remain to be fully delineated but anergy, deletion, immune deviation and Treg induction all seem contributory to successful outcomes, with changes in IgG4 apparently less important compared to conventional AIT. T cell epitope peptide therapy is promising a safe and effective new class of specific treatment for allergy, enabling wider application even for more severe allergic diseases.

Current developments for improving efficacy of allergy vaccines

“…The most exciting advance in modification of allergen form for treatment of allergic diseases has been with the use of sets of short allergen-derived peptides, carefully selected and designed to comprise the dominant T-cell-reactive sites of the major allergen sequences but lacking IgE binding and inflammatory cell-activating potential [117]. The concept of using T-cell epitope peptides to induce anergy in allergen-specific T cells was first introduced in the 1990s by O'Hehir and collaborators, when short-term incubation of clonal Der p 1-specific T cells with high concentration of a dominant T-cell epitope peptide of Der p 1 was found to induce a state of non-responsiveness in the T cells to subsequent challenge with immunogenic concentrations of that peptide, or indeed whole HDM [118].…”

T‐cell activation by transgenic rice seeds expressing the genetically modified Japanese cedar pollen allergens

“…We further identified various types of T-cells induced in Cry j 1-or Cry j 2-immunized mice by using overlapping peptides spanning the Cry j 1 or Cry j 2 sequences. 18 In Japan, SCIT and SLIT have been applied to treat JC pollinosis. However, these results did not necessarily confirm that TG-rice seeds contained a specific epitope of Cry j 1 or Cry j 2.…”

Human memory CD4+ T cell response to the major dog allergen Can f 5, prostatic kallikrein

“…In the most severe cases, systemic or even life-threatening reactions, such as anaphylaxis, may occur [30,31]. In the most severe cases, systemic or even life-threatening reactions, such as anaphylaxis, may occur [30,31].…”