Factors Influencing the Allergenicity and Adjuvanticity of Allergens

Stephan Deifl; Barbara Bohle

Disclosures

Immunotherapy. 2011;3(7):881-893. 

In This Article

Adjuvanticity

As pointed out previously, several major allergens may have special properties that contribute to their capacity to induce specific IgE responses in susceptible individuals. In SIT, crude allergen extracts are administered to allergic patients to achieve the modulation of the disease-eliciting allergic response towards a more balanced immune response. Because the administration of allergens to allergic patients can induce undesired side effects, conventional SIT is usually started with very low doses of allergen extracts. The steady increase of allergen doses during the early phase of SIT induces tolerance and allows the administration of a clinically effective maintenance dose, which is then continuously applied for 3–5 years. Still, SIT is not effective in every treated patient. To improve the curative efficacy of allergen vaccines, aluminum hydroxide (Alum) is used as adjuvant in European vaccines for subcutaneous SIT. Alum absorbs proteins and slowly releases them in vivo, which increases the stability of administered allergens. In addition to this antigen delivery function, Alum triggers innate immune pathways, thereby generating an immunocompetent environment at the injection site. More precisely, Alum activates a protein complex called NLPR3/inflammasome, which is required for correct processing of a number of proinflammatory cytokines.[87–89] Of note, in mouse models of allergy, allergens need to be adsorbed to Alum to achieve the induction of allergen-specific Th2 responses. This observation raised fears that Alum may also foster Th2-like responses in humans. So far, one study has addressed this issue in vitro. When human peripheral blood mononuclear cells (PBMCs) were cultured with allergens plus Alum, a significant decrease in both IL-5 and IL-13 production compared with allergen alone, but no changes in IFN-γ or IL-12 production or proliferative responses were observed.[90] Thus, Alum downregulated allergen-driven Th2 responses while Th1 cytokines were unaffected, indicating that it is a reasonable adjuvant for SIT.

In view of the immunomodulation induced during SIT (i.e., the induction of Th1-like responses and Treg cells resulting in blocking antibodies), the concept emerged to employ new adjuvant substances in allergy vaccines that should particularly promote these desired immune mechanisms. Up to now, two adjuvant substances have been evaluated in clinical trials, monophosphoryl lipid (MPL)-A, a nontoxic component of LPS, and immunostimulatory sequences of bacterial DNA.[91] MPL-A, which is commonly added to different allergen extracts, is recognized by TLR4 and induces the production of various proinflammatory and inflammatory cytokines including IL-12 and IL-18 that promote Th1 responses. Indeed, mixtures of allergen extracts and MPL-A have been shown to promote allergen-specific Th1-responses in PBMCs from allergic patients.[92] Moreover, patients treated with MPL-A-containing vaccines developed allergen-specific IgG antibodies with blocking capacity.[93,94] Immunostimulatory DNA sequences containing CpG motifs are recognized by TLR9 and induce B-cell activation, Th1 cytokines and the maturation of DCs.[95–97] Also, PBMCs from allergic individuals responded with the production of IL-12, IL-18 and IFN-γ and a reduced IgE synthesis.[98] Studies with immunostimulatory DNA sequences chemically linked to allergens have taught us that allergen–adjuvant conjugates are more effective than mixtures of both components.[99] The increased immunogenicity of allergen–adjuvant conjugates may be referred to allergen uptake and presentation by the same APC that responds to the danger signal. Thereby, the activated APC efficiently primes naive T cells in a cytokine-loaded environment that fosters their differentiation into Th1 and Treg cells, respectively. Immunostimulatory DNA sequences chemically linked to the major ragweed allergen Amb a 1 have been tested in clinical trials but are not commercially available.[100]

The idea of linking adjuvants directly to allergens was successfully achieved by applying DNA technology to produce recombinant allergens. Different fusion proteins consisting of recombinant allergens and molecules with adjuvant activity were engineered.[101] For example, allergens were fused with the subunit B of cholera toxin, an efficient mucosal carrier, to support tolerance induction[102] or with diphtheria toxin protein to exert specific toxicity to cells.[103] A big advantage of recombinant fusion proteins is their constant ratio between allergen and adjuvant resulting in persistent immunological activity. Thereby, batch-to-batch variations are avoided. Moreover, some of the fusion proteins showed a reduced IgE-binding capacity as compared with the nonfused allergen. These hypoallergenic proteins should induce less IgE-mediated side effects when administered during SIT. Recently, TLR ligands were also fused with allergens and tested for their immunological features. Two examples of such recombinant allergen–adjuvant fusion proteins will be introduced in the following sections.

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