Hymenoptera Venom Immunotherapy

Beatrice M Bilò; Floriano Bonifazi

Disclosures

Immunotherapy. 2011;3(2):229-246. 

In This Article

Future Perspective

Modern molecular biology has provided us with a considerable number of major honeybee and various vespid venom allergens in recombinant form,[121,122] whose use greatly enhances the accuracy of the diagnosis.[34–36] Recombinant venom allergens may pave the way towards novel future therapeutic techniques, even though they have yet to be used for VIT.

Major T-cell epitope peptides can be prepared synthetically or expressed as recombinant fragments. A mixture of three dominant T-cell peptides of phospholipase (PLA) has, so far, only been used for immunotherapy in a preliminary bee venom allergy study in five patients where complete protection was bestowed in three subjects and partial protection in the remaining two after a bee sting challenge with no side effects.[123]

In a double-blind, randomized, placebo-controlled trial in bee venom allergic patients, using three long, synthetic, overlapping peptides (LSPs), mapping the entire PLA2 amino acid sequence, this therapy induced T-cell anergy, immune deviation toward a Th1-type T-cell cytokine response, enhanced IL-10 secretion, and PLA2-specific IgG4 production. LSP immunotherapy was safe and did not cause any severe systemic reactions. The efficacy of treatment with these long peptides, however, was not verified by a sting challenge.[124]

DNA vaccination is where DNA plasmids encoding the relevant allergens are injected. The successful DNA vaccination of sensitized mice has, among other allergens, been reported with plasmids from bee venom PLA2.[125] To date, DNA vaccination for VIT has not been tested in a human model.

However, many hymenoptera venom-allergic patients are sensitized to more than one vespid or honeybee venom allergen, signifying that treatment with one major allergen in recombinant unrefolded or point mutated form, with peptides or DNA plasmids encoding it, may be insufficient. A fusion protein composed of the two major allergens of bee venom PLA2 and hyaluronidase (HYA) was constructed through genetic engineering and characterized by destroyed conformational B-cell epitopes but intact T-cell epitopes of the two allergens.[126] The fusion protein induced T-cell proliferation and both Th1- and Th2-type cytokine responses; on the other hand, IgE reactivity was abolished and basophil degranulation reduced. The use of the fusion protein for VIT could minimize anaphylactic side effects and increase efficacy compared with the whole-venom-based treatment.[126]

Another model used a recombinant chimeric protein consisting of the whole amino acid sequences of three major bee venom allergens (PLA2, HYA and melittin). The fragments were designed to preserve all relevant T-cell epitope peptides while conformational B-cell epitopes were destroyed.

Use of this chimeric protein in mouse models has led to a significant reduction of specific IgE development towards the native allergen, which has produced a protective vaccine effect in vivo.[127]

Finally, the intralymphatic allergen administration for specific immunotherapy has been recently proposed in grass pollen allergic rhinitis. Compared with a 3-year course of conventional subcutaneous immunotherapy, intralymphatic application enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks.[128] The therapeutic potential of bee venom intralymphatic immunization was then analyzed in sensitized mice using an anaphylaxis model.[129] Direct injection of the major bee venom allergen phospholipase A2 into inguinal lymph nodes enhanced allergen-specific IgG and T-cell responses when compared with subcutaneous injections. Moreover, only intralymphatic immunization stimulated the production of the Th1-dependent subclass IgG2a, which is associated with improved protection against allergen-induced anaphylaxis. The authors concluded that this approach should improve both the efficacy and safety of VIT.[129] Similar studies in humans, including clinical parameters and sting challenges, are needed to assess the effectiveness of this route of allergen administration.

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