Evolution of subcutaneous allergen immunotherapy (part 1): from first developments to mechanism-driven therapy concepts

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

The regulation of normal and allergic immune responses to airborne allergens in the mucosa is still poorly understood, and the mechanism of specific immunotherapy (SIT) in normalizing the allergic response to such allergens is currently not clear. Accordingly, we have investigated the immunoregulatory mechanism of both normal and allergic responses to the major house-dust mite (HDM) and birch pollen allergens--Dermatophagoides pteroynyssinus (Der p)1 and Bet v 1, respectively--as well as the immunologic basis of SIT to HDM in rhinitis and asthma patients. In normal immunity to HDM and birch pollen, an allergen-specific peripheral T cell suppression to Der p 1 and Bet v 1 was observed. The deviated immune response was characterized by suppressed proliferative T cell and Th1 (IFN-gamma) and Th2 (IL-5, IL-13) cytokine responses, and increased IL-10 and TGF-beta secretion by allergen-specific T cells. Neutralization of cytokine activity showed that T cell suppression was induced by IL-10 and TGF-beta during SIT and in normal immunity to the mucosal allergens. In addition, SIT induced an antigen-specific suppressive activity in CD4(+) CD25(+) T cells of allergic individuals. Together, these results demonstrate a deviation towards a regulatory/suppressor T cell response during SIT and in normal immunity as a key event for the healthy immune response to mucosal antigens.

Allergic diseases are frequent and rising in prevalence, and result from activation of T-helper (Th) 2 cells by allergens. CD4+CD25+ regulatory T cells suppress T-cell activation in vitro and prevent pathological findings in animal models of disease. We aimed to investigate whether the amount of inhibition of allergic responses by CD4+CD25+ T cells was related to atopy and allergic disease. Blood CD4+CD25+ and CD4+CD25- T cells were isolated from three groups of donors: non-atopic individuals; those atopic with no present symptoms; and patients with hayfever studied during and out of the grass-pollen season. We investigated the ability of CD25+ T cells from these donors to suppress allergen-stimulated T-cell proliferation and cytokine production in vitro. CD4+CD25+ T cells from non-atopic donors suppressed proliferation and interleukin 5 production by their own allergen-stimulated CD4+CD25- T cells. Inhibition of proliferation by CD4+CD25+ T cells from atopic donors was significantly reduced (p=0.0012), and was even more diminished by CD4+CD25+ T cells isolated from patients with hayfever during the pollen season (p=0.0003). In patients with hayfever, out-of-season suppression remained less than that seen by regulatory cells from non-atopic donors. Allergic disease can result from an inappropriate balance between allergen activation of regulatory CD4+CD25+ T cells and effector Th2 cells. This imbalance could result from a deficiency in suppression by regulatory T cells or strong activation signals could overcome such regulation. Treatment to enhance regulatory T-cell responses, in concert with reduction of Th2 cell activation, might be useful in prevention and treatment of allergic disease.