Blocking antibodies induced by peanut oral and sublingual immunotherapy suppress basophil activation and are associated with sustained unresponsiveness

Abstract

Background: Oral and sublingual immunotherapies for peanut allergy have demonstrated efficacy in small clinical trials; however, mechanisms and biomarkers correlating with clinical outcomes remain elusive. Previous studies have demonstrated a role for IgG in post-OIT plasma in the suppression of IgE-mediated mast cell reactions. Objective: The aim of this study was to characterize the role that peanut oral and sublingual immunotherapy-induced plasma factors play in the inhibition of ex vivo basophil activation and whether inhibitory activity is associated with clinical outcomes. Methods: Plasma samples from subjects on placebo, peanut oral immunotherapy (OIT) or peanut sublingual immunotherapy (SLIT), and IgG-depleted plasma or the IgG fraction were incubated with sensitized basophils, and the inhibition of basophil activation following stimulation with peanut extract was measured. Basophil inhibition results were compared between the two routes of immunotherapy, time on treatment and clinical outcomes. Results: Plasma from subjects after 12 months of active peanut OIT, but not placebo, inhibits basophil activation ex vivo. Depletion of IgG abrogated the blocking effect of OIT plasma, while the IgG fraction substantially blocked basophil activation. Basophils are inhibited to a similar extent by undiluted OIT and SLIT plasma; however, diluted OIT plasma from the time of desensitization challenge inhibited basophils more than diluted SLIT plasma from time of desensitization challenge.Plasma from subjects who experienced sustained unresponsiveness following OIT inhibited basophils to a greater extent than plasma from subjects who were desensitized, but this was not true for SLIT. Conclusions and ClinicalRelevance: Peanut immunotherapy induces IgG-dependent functional changes in plasma that are associated with OIT but not SLIT clinical outcomes. Understanding the mechanisms of peanut OIT and SLIT may help derive informative biomarkers. K E Y W O R D S basophil activation, food allergy, IgG, immunoglobulin, immunotherapy, peanut allergy

Sustained successful peanut oral immunotherapy associated with low basophil activation and peanut-specific IgE

“…Depletion of IgG, specifically IgG 4 , has been shown to eliminate the inhibitory effect of OIT plasma in basophil activation. 28,40,44 We did not find direct associations between peanut-induced % CD63 high basophils and levels of peanut sIgG 4 alone; however, we detected significant but weak correlations between peanut-induced %CD63 high basophils and sIgG 4 /sIgE before and after OIT, as well as a moderate correlation between peanut-induced %CD63 high basophils and sIgE/total IgE after OIT. These findings suggest that basophil activation is regulated by the summation of activating (such as sIgE) and inhibitory (eg, IgG 1 and IgG 4 ) immunoglobulins.…”

“…21,22 Some studies have suggested that BATs are more reliable than skin prick tests and sIgE levels in differentiating food allergy from tolerance in children. 32,34 Although suppression of basophil activation by immunotherapy has been demonstrated in food allergy to egg, 37 milk, 38 and peanut, 7,8,18,[25][26][27]39,40 only a few studies have examined the association of basophil activation with treatment outcomes. 18,26,27,37,40,41 Our analysis of BAT results obtained for more than 2 years in the POISED study shows that basophil activation remains suppressed even after 13 weeks off active OIT, and that sustained protection is associated with lower levels of basophil activation by peanut before, during, and after OIT.…”

Peanut oral immunotherapy induces blocking antibodies but does not change the functional characteristics of peanut-specific IgE

“…Our findings support the induction of blocking antibodies with POIT, as previously reported by us 2 and others, 6,7 and demonstrate, for the first time, that POIT did not change the functional characteristics of IgE, as determined by the ability of effector cells, such as mast cells and basophils, to respond to peanut allergens with cellular activation, degranulation, mediator release, and consequent acute allergic reactions to peanut. The enhanced mast cell response to anti-IgE after POIT suggests that continued exposure to the allergen can potentiate IgE-mediated mast cell responses.…”

“…Toll-like receptors. 7 These findings suggest that TNF, together with other innate cytokines, including IL-33, might play a role in protection from helminth infection through activation of ILC2s.…”

The chicken or the egg?

“…Orgel et al have investigated the mechanisms of action of oral immunotherapy (OIT) for peanut allergy . We know that specific IgG levels increase post‐OIT but whether this underlies the clinical impact of OIT is unclear.…”