Current and Emerging Immunotherapeutic Approaches to Treat and Prevent Peanut Allergy

Darren S Miller; Michael P Brown; Paul M Howley; John D Hayball

Disclosures

Expert Rev Vaccines. 2012;11(12):1471-1481. 

In This Article

Immunotherapeutic Approaches to Peanut Allergy

Immune Deviation Strategies

The defining immunopathologic feature of peanut allergy is the presence of circulating peanut protein-specific IgE antibodies in the susceptible individual. Therefore, any approach that reduces the levels of IgE has the potential to reduce allergic sensitivity. However, unlike traditional immunotherapy for allergic reactions to inhalants such as grass pollens, dust mite and bee sting venom, subcutaneous desensitization injections of peanut extracts have an unacceptable risk–benefit ratio.[60]

Another approach may be to reprogram the immune response in a TH1 or cell-mediated direction. Cell-mediated immunity is usually elicited in response to endogenous peptides, which for example may be derived from proteins synthesised within cells during a viral infection. Here, a finite amount of newly synthesised endogenous protein is degraded within the cell by the proteasome to produce 8-12mer peptides, which are delivered into the endoplasmic reticulum (ER) where they associate with MHC class I molecules on their way to the cell surface. CD8+ T lymphocytes recognize the cell-surface MHC I/peptide complexes and release TH1 cytokines, which mature CD8+ T lymphocytes into CTLs.[61] Activated CTLs subsequently recognize cells bearing cognate MHC I/peptide complexes and target them for destruction.

Exogenous proteins, which usually enter the MHC class II processing pathway, can be cross presented on MHC class I molecules by entering the MHC class I processing pathway, but only by immature DCs, which is a unique and highly specialized APC.[62–65] Simultaneous presentation via MHC I and MHC II pathways will activate CD8+ and CD4+ T cells to secrete TH1 cytokines that will stimulate B cells to produce and secrete antigen-specific IgG2 antibodies. Because they do not bind to mast cells or basophils, these types of antibodies play no role in the induction of an allergic reaction although they do bind and neutralize pathogens and toxins, thus clearing them from the host.

In contrast, food allergens are presented to the immune system as exogenous peptides. Hence, in order to generate a TH1-biased immune response to food allergens, immunization protocols must aim at intracellular delivery of the allergen, so that entry into the MHC class I processing can occur directly or indirectly via cross presentation. Consequently, TH1-directed switching to IgG class might neutralize peanut proteins and suppress peanut-specific IgE antibody levels. Together, this maneuver has the potential to provide protection in those individuals predisposed to peanut allergy (i.e., those with family history of peanut allergy or known atopic individuals) and, importantly, a therapeutic immune response in those with pre-existing peanut allergy.

DNA Immunization

Immunization with plasmid DNA encoding food allergens is a good example of this kind of approach of targeting antigen to the MHC class I processing pathway. The DNA vaccine is taken up by APCs where the DNA encoding allergen is transcribed, translated, and presented by MHC class I molecules to the APC surface to T cells. This endogenously produced allergic protein or protein fragment induces a TH1 phenotypic response with up-regulation of TH1 cytokines, an increase in IgG2 antibodies and suppression of allergen specific IgE antibody production.[66,67]

The concept that immunizing with DNA coding for allergens might present a new approach to immunotherapy for allergic diseases was first described over 15 years ago,[68] and the first practical example of this approach, which demonstrated alleviated responses, was to the house dust mite allergen Der p5.[69] Here it was shown that in rats immunized with plasmid DNA encoding Der p5, that sustained antigen expression was evident and that it induced antigen-specific immune responses that inhibited IgE production and histamine release in bronchio-alveolar fluid. Airway hyper-responsiveness in rats challenged with aerosolized allergen was also suppressed and this suppression was persistent; when CD8+ T cells from these immunized rats were transferred into naive rats, IgE synthesis was inhibited.

Another DNA immunization technique under investigation is immunization with plasmid DNA that coexpress to immunostimulatory sequences. These stimulate APCs and natural killer cells to secrete TH1 cytokines that promote immune deviation toward the TH1 phenotype and away from the allergic TH2 phenotype.[70] Most of these DNA immunization techniques have been studied in murine models. However, in a seminal study involving mice and rabbits, as well as in primates, it was shown that immune deviation was toward a TH1 phenotype and a reduction in allergenicity was possible after injection immunotherapy with the major ragweed allergen, Amb a 1, conjugated to immunostimulatory sequences.[71]

The high amount of plasmid DNA necessary for vaccination still remains the major shortcoming of this approach for allergy treatment in humans and clinical trials with DNA vaccines indicate poor immunogenicity of the constructs in humans.[72] However, the use of live viral vaccine vectors for delivery and expression of antigens in infectious diseases and cancer vaccination studies are starting to show promise,[73–75] and this approach has potential applications in peanut immunotherapy.

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