Specific allergen immunotherapy is clinically effective and has benefit that extends beyond the treatment period (1). Unlike conventional pharmacotherapy, specific allergen immunotherapy is disease modifying and has been shown to prevent the development of asthma (2) and to reduce sensitizations to other allergens (3). Optimal treatment times vary based on allergen and therapeutic preparation, but in general terms, a course of 3 years therapy is regarded as optimal. Although there are no formal published data on the relationship between treatment time and duration of clinical response, it is widely held that clinical benefit will last for twice as long as the treatment period. Thus, treatment for 1 year results in additional benefit for the subsequent year, whereas treatment for 3 years will provide clinical benefit for a further 3 years. The lengthy duration of treatment, the frequent administration of allergen and the associated high frequency of allergic adverse events, which may be systemic and in some cases lifethreatening, have limited uptake of this form of therapy. These shortcomings are the result of the allergenicity of the preparations employed for therapy. These contain whole allergen molecules with intact B-cell epitopes that are readily able to crosslink specific IgE molecules on the surface of effector cells (Fig. 1). A number of strategies aimed at reducing the allergenicity of treatment preparations, whilst maintaining immunogenicity, have been described. Physical modification of allergen molecules may reduce or eliminate IgE reactivity and thus allergenicity (4). Such approaches have taken many forms including chemical modification, conjugation with synthetic bacterial DNA motifs, point mutations in native allergen gene sequences and the use of allergen multimers, fragments and peptides of various lengths. The use of soluble, short synthetic peptides for the treatment of allergic disease allows the delivery of T-cell epitopes of the allergen in an adjuvant-free, tolerogenic form, whilst avoiding IgE-mediated allergic reactions (5, 6). Synthetic peptides have been developed and evaluated in both experimental animal models and human clinical studies. Synthetic peptides are defined active pharmaceutical ingredients (API) and can be produced in a reproducible and standardized fashion that cannot be achieved with allergen extracts. Further advantages include low production costs, ease of purification and good stability in lyophilized form without the need for cold storage. Presentation of T-cell epitopes to T cells by nonprofessional antigen-presenting cells (APC) results in the induction of 'anergy', a term describing antigen-specific nonresponsive- AbstractSpecific allergen immunotherapy is clinically effective and disease modifying. It has a duration of effect that exceeds the treatment period and prevents both the progression of allergic rhinitis to asthma and the acquisition of new allergic sensitizations. However, immunotherapy is associated with a high frequency of adverse events related to ...

Inflammation is a hallmark of many airway diseases. Improved understanding of the cellular and molecular mechanisms of airway disease will facilitate the transition in our understanding from phenotypes to endotypes, thereby improving our ability to target treatments based on pathophysiologic characteristics. For example, allergic asthma has long been considered to be driven by an allergen-specific T helper 2 response. However, clinical and mechanistic studies have begun to shed light on the role of other cell subsets in the pathogenesis and regulation of lung inflammation. In this review, we discuss the importance of different lymphocyte subsets to asthma and other airway diseases, while highlighting the growing evidence that asthma is a syndrome that incorporates many immune phenotypes.

These observations suggest that immune tolerance induced by peptide immunotherapy can be used experimentally to treat an allergic response to another allergen and that the molecular mechanisms underlying induction of tolerance to a treatment-specific allergen and a bystander allergen might be different.

In the present study, we show therapeutic amelioration of established ovalbumin (OVA)-induced allergic airway disease following house dust mite (HDM) peptide therapy. Mice were sensitized and challenged with OVA and HDM protein extract (Dermatophagoides species) to induce dual allergen sensitization and allergic airway disease. Treatment of allergic mice with peptides derived from the major allergen Der p 1 suppressed OVA-induced airway hyperresponsiveness, tissue eosinophilia, and goblet cell hyperplasia upon rechallenge with allergen. Peptide treatment also suppressed OVA-specific T-cell proliferation. Resolution of airway pathophysiology was associated with a reduction in recruitment, proliferation, and effector function of T(H)2 cells and decreased interleukin (IL)-17⁺ T cells. Furthermore, peptide immunotherapy induced the regulatory cytokine IL-10 and increased the proportion of Fox p3⁺ cells among those expressing IL-10. Tolerance to OVA was not associated with increased IL-35. In conclusion, our results provide in vivo evidence for the creation of a tolerogenic environment following HDM peptide immunotherapy, leading to the therapeutic amelioration of established OVA-induced allergic airway disease.

Allergy 71 (2016) 283-285

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