Allergen immunotherapy: past, present and future

Abstract

Allergen immunotherapy is a form of therapeutic vaccination for established IgE-mediated hypersensitivity to common allergen sources such as pollens, house dust mites and the venom of stinging insects. The classical protocol, introduced in 1911, involves repeated subcutaneous injection of increasing amounts of allergen extract, followed by maintenance injections over a period of 3 years, achieving a form of allergen-specific tolerance that provides clinical benefit for years after its discontinuation. More recently, administration through the sublingual route has emerged as an effective, safe alternative. Oral immunotherapy for peanut allergy induces effective 'desensitization' but not long-term tolerance. Research and clinical trials over the past few decades have elucidated the mechanisms underlying immunotherapy-induced tolerance, involving a reduction of allergen-specific T helper 2 (T_H2) cells, an induction of regulatory T and B cells, and production of IgG and IgA 'blocking' antibodies. To better harness these mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance; these include alternative routes for current immunotherapy approaches, novel adjuvants, use of recombinant allergens (including hypoallergenic variants) and combination of allergens with immune modifiers or monoclonal antibodies targeting the T_H2 cell pathway.

Fig. 1. Key milestones in allergen immunotherapy.

HDM, house dust mite.

Fig. 2. Mechanisms of allergic inflammation and immunotherapy.

Allergic inflammation involves IgE-dependent activation of mast cells and local tissue eosinophilia under the regulation of T helper 2 (T_H2)-type cytokines (IL-4, IL-5, IL-9 and IL-13). The innate immune system, including specialized subsets of dendritic cells and innate lymphoid cells (ILCs), has a role in both induction and regulation of allergen-induced T_H2-type responses. These innate cells are under the influence of epithelial cell-derived cytokines including thymic stromal lymphopoietin (TSLP), IL-25 and IL-33. In individuals with atopic allergy, type 2 dendritic cells (DC2s) preferentially induce the differentiation of T_H2 cells and a population of allergen-stimulated T_H2 cells defined by high expression of CRTH2 and CD161 and low expression of CD27 (CRTH2⁺CD161⁺CD27^–; referred to as T_H2A cells). A further subset of cells expressing T_H2-type cytokines are type 2 T follicular helper (T_FH) cells, which derive from the marginal zones of lymph nodes. Allergen–IgE cross-linking of adjacent high-affinity IgE receptor (FcεRI) receptors on mast cells releases granule-derived mediators, such as tryptase and histamine, and membrane-associated lipid mediators that include prostaglandin D2 (PGD₂) and sulfidopeptide leukotrienes. Allergen–IgE complexes also bind to surface low-affinity receptor for IgE (FcεRII) on B cells that results in IgE-facilitated T_H2 cell development^,. During subcutaneous immunotherapy and sublingual immunotherapy, high-dose allergen exposure restores regulatory dendritic cells^, that produce IL-10 (refs.^,) and IL-12 (refs.^,), inhibits T_H2 cell responses^, and promotes regulatory T (T_reg) cell^, and regulatory B (B_reg) cell^, responses and immune deviation in favour of a T_H1 cell response^,. There is preferential B cell isotype switching towards IgG and IgA^,, resulting in IgE-blocking activity^,,, which inhibits both IgE-mediated activation of mast cells and basophils and IgE-facilitated antigen presentation and T_H2 cell responses^,. Red arrows indicate suppressive activities of T_reg cells and B_reg cells, and IgG/IgA-associated IgE blocking activity. CTLA4, cytotoxic T lymphocyte antigen 4; iDC, immature dendritic cell; MCT, microcrystalline tyrosine; nT_reg cell; thymus-derived natural regulatory T cell; PRR, pattern recognition receptor; TCR, T cell receptor; TGFβ, transforming growth factor-β; TLR, Toll-like receptor; T_R1 cell, type 1 regulatory T cell (characterized by the co-expression of CD49b and LAG3) .

Fig. 3. Current and novel approaches of allergen immunotherapy.

At present, long-term tolerance for inhalant allergies may only be achieved by allergen immunotherapy with standardized whole allergen extracts via either subcutaneous or sublingual routes. To better harness the known underlying mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance. These include the combination of allergen extract with monoclonal antibodies (mAbs) directed against the T helper 2 (T_H2) cell pathway, or with immune modifiers such as Toll-like receptor (TLR) agonists. Molecular allergology has enabled more accurate allergy diagnosis and the development of recombinant whole allergens and hypoallergenic variants that, in the future, may result in a more individualized ‘tailor-made’ allergen immunotherapy. Allergen-derived peptides have been developed to target specifically underlying T or B cell-dependent pathways. These are likely to be safer, although so far they have not shown greater efficacy over whole allergen approaches that target both pathways. On the basis of the known ability of allergen immunotherapy to induce IgE-blocking antibodies, passive immunotherapy by injection of cocktails of IgG4 monoclonal antibodies directed against IgE epitopes of major allergens has proved successful in inhibiting human nasal allergen challenge responses. Oral immunotherapy in children with peanut allergy has been highly effective in inducing ‘desensitization’, whereas long-term tolerance remains elusive, and the treatment is accompanied by occasional serious systemic side effects. Earlier intervention in infancy and early childhood and/or the use of allergen combination strategies may overcome these problems. The epicutaneous approach using peanut allergen patches may be less effective in desensitization but is able to reduce the risk of anaphylaxis on exposure to traces of peanut and this may be a more feasible approach, with lower risk of treatment-related systemic side effects. B_reg cell, regulatory B cell; FcεRII, low-affinity receptor for IgE; IL-4R, interleukin-4 receptor; T_reg cell, regulatory T cell; TSLP, thymic stromal lymphopoietin.