Hymenoptera Venom Immunotherapy: Immune Mechanisms of Induced Protection and Tolerance

Abstract

Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure long-term tolerance post-therapy.

Time-dependent effect of desensitization with wasp venom on selected parameters of the immune system

“…The percentage of nTreg was increased after VIT treatment which was especially seen 24 weeks post-treatment. This is similar to other authors, which described the elevated level of natural and induced Treg cells in peripheral blood after VIT treatment 21 – 24 . The question arises when an organism enables the increase of nTreg cells production.…”

Intralymphatic Immunotherapy (ILIT) With Bee Venom Allergens: A Clinical Proof-of-Concept Study and the Very First ILIT in Humans

“…Venom immunotherapy has been associated with increased IgGs ( 13 , 35 – 38 ), and with higher doses producing higher IgG titers ( 39 ) although it is not clear if IgG levels correlate with sting protection ( 40 – 43 ). In both presented ILIT trials, we observed enhanced bee venom-specific IgG antibody levels but no significant difference in IgG levels in protected and in non-protected patients could be detected.…”

Natural and Induced Tolerance to Hymenoptera Venom: A Single Mechanism?

“…Another tolerogenic mechanism of AIT is the isotype switching from sIgE to sIgG4. It has been previously described that VIT produces an initial increase in sIgE levels followed by a decrease over the years, associated with a progressive increase in sIgG4 [ 34 , 35 ]. In our study, there was an early increase of sIgE at the end of up-dosing to all bee venom molecular components, significant for rApi m 1, rApi m 3, Api m 4, rApi m 5, and rApi m 10, with a decrease evident in T3.…”