Hymenoptera Venom Immunotherapy

Beatrice M Bilò; Floriano Bonifazi

Disclosures

Immunotherapy. 2011;3(2):229-246. 

In This Article

Mechanisms of Action of VIT

The underlying immunological mechanisms of VIT are continuously being elucidated. Different mechanisms involving specific cell populations, play a role in the different phases of VIT,[12] even though some described events may represent epiphenomena rather than causative events. Peripheral T-cell tolerance represents an essential step in successful VIT, and it is mainly characterized by generation of allergen-specific Treg cells, with suppressed proliferative and cytokine responses against the major allergen.[13] This is initiated by autocrine action of IL-10 and TGF-β that are increasingly produced by the antigen-specific Tr1 cells,[14–16] which express CD4 and CD25. This finding raises the question as to whether these are inducible Tr1 cells, which have upregulated CD25 or naturally occurring CD4+CD25+ Treg cells that produce suppressive cytokines.[17] There is some evidence in adults that circulating CD4+CD25+ Treg cells and IL-10- and TGF-β-secreting Tr1 cells represent overlapping populations, and that CD4+CD25+ Treg cells from atopic donors have a reduced capability to suppress the proliferation of CD4+CD25 T cells following allergen immunotherapy.[17,18] It has been suggested that upregulation of CD4+CD25+ Treg cells plays a role in allergen immunotherapy. Accordingly, using an ultrarush protocol in vespid allergic patients, an increase in CD4+CD25+ Treg cells and IL-10-producing T cells has been demonstrated in the hours following the commencement of VIT.[19]

Although peripheral tolerance has been demonstrated in specific T cells, the ability of B cells to produce specific IgE antibodies is not eliminated during allergen immunotherapy.[13] The effects of VIT on venom-specific IgE and IgG antibodies are well documented,[2] although neither concentration (or a change in concentration) of IgG nor the IgE:IgG ratio correlate closely with the clinical response to immunotherapy.[10] The proposal of blocking antibodies has been re-evaluated on the basis of observations of altered specificity and affinity during immunotherapy and effects on memory B cells and antigen-presenting cells.[20] IL-10, produced and progressively secreted during allergen immunotherapy, appears to counter-regulate synthesis of antigen-specific IgE and IgG4 antibodies. IL-10 potently suppresses both total and allergen-specific IgE while simultaneously increasing IgG4 production.[15,21] Therefore, IL-10 not only generates T-cell tolerance but it also regulates specific isotype formation and skews the specific IgE response towards an IgG4-dominated phenotype.

Very early effects of VIT are also associated with an early decreased mediator release from mast cells and basophils, although the mechanism of this desensitization effect is, as yet, unknown.[12,22] Ultrarush protocols significantly increase the release of mediators of anaphylaxis into circulation without inducing a systemic anaphylactic response in the majority of cases. This piecemeal release of mediators may decrease the granule content of mediators and affect the threshold of mast-cell and basophil activation.[12,23] An increase in intracellular cAMP levels immediately after vespid rush VIT, parallel to a decrease of allergen-induced release of histamine and sulfidoleukotrienes from basophils, was demonstrated;[24] this intracellular modification might account for the decreased reactivity of basophils to allergen following 1 week of VIT, although this seems not to be a long-term effect as values returned to baseline after 6 months.[24]

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