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Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy.

ABSTRACT: Monoclonal antibodies directed at IgE demonstrate clinical efficacy in subjects with peanut allergy, but previous studies have not addressed the kinetics of the clinical response or the role of mast cells and basophils in the food-induced allergic response.We sought to determine the kinetics of the clinical response to omalizumab and whether clinical improvement is associated with either mast cell or basophil suppression.Subjects with peanut allergy were treated with omalizumab for 6 months and assessed for clinical and cellular responses. At baseline, subjects had a double-blind, placebo-controlled oral food challenge (OFC), skin prick test titration (SPTT), and basophil histamine release (BHR) to peanut. BHR was repeated at week 2 and then weekly until it decreased to less than 20% of baseline values. The OFCs and SPTTs were repeated after the BHR reduction (or at week 8 if BHR did not decrease) and again at 6 months.Fourteen subjects enrolled in the study. At the second food challenge, there was a significant increase in the threshold dose of peanut inducing allergic symptoms (80 to 6500 mg, P < .01). Peanut-induced BHR was either completely suppressed (n = 5) or 10-fold more allergen was required to induce maximal BHR (n = 9), and SPTT responses were not significantly changed from baseline. After 6 months of omalizumab, further changes in the OFC threshold dose or BHR were not observed, but a significant suppression in SPTTs was identified.The clinical response to omalizumab occurs early in treatment when the basophil, but not the mast cell, is suppressed, supporting a role for the basophil in acute food reactions.

SUBMITTER: Savage JH

PROVIDER: S-EPMC3935509 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy.

Savage Jessica H JH Courneya Jean-Paul JP Sterba Patricia M PM Macglashan Donald W DW Saini Sarbjit S SS Wood Robert A RA

The Journal of allergy and clinical immunology 20120715 5

<h4>Background</h4>Monoclonal antibodies directed at IgE demonstrate clinical efficacy in subjects with peanut allergy, but previous studies have not addressed the kinetics of the clinical response or the role of mast cells and basophils in the food-induced allergic response.<h4>Objective</h4>We sought to determine the kinetics of the clinical response to omalizumab and whether clinical improvement is associated with either mast cell or basophil suppression.<h4>Methods</h4>Subjects with peanut a ...[more]

PMID: 22800401

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Project description:Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, Fc?RI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, Fc?RIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signals via Fc?RIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signaling via Fc?RIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.

Project description:BackgroundMost children with detectable peanut-specific IgE (P-sIgE) are not allergic to peanut. We addressed 2 non-mutually exclusive hypotheses for the discrepancy between allergy and sensitization: (1) differences in P-sIgE levels between children with peanut allergy (PA) and peanut-sensitized but tolerant (PS) children and (2) the presence of an IgE inhibitor, such as peanut-specific IgG4 (P-sIgG4), in PS patients.MethodsTwo hundred twenty-eight children (108 patients with PA, 77 PS patients, and 43 nonsensitized nonallergic subjects) were studied. Levels of specific IgE and IgG4 to peanut and its components were determined. IgE-stripped basophils or a mast cell line were used in passive sensitization activation and inhibition assays. Plasma of PS subjects and patients submitted to peanut oral immunotherapy (POIT) were depleted of IgG4 and retested in inhibition assays.ResultsBasophils and mast cells sensitized with plasma from patients with PA but not PS patients showed dose-dependent activation in response to peanut. Levels of sIgE to peanut and its components could only partially explain differences in clinical reactivity between patients with PA and PS patients. P-sIgG4 levels (P = .023) and P-sIgG4/P-sIgE (P < .001), Ara h 1-sIgG4/Ara h 1-sIgE (P = .050), Ara h 2-sIgG4/Ara h 2-sIgE (P = .004), and Ara h 3-sIgG4/Ara h 3-sIgE (P = .016) ratios were greater in PS children compared with those in children with PA. Peanut-induced activation was inhibited in the presence of plasma from PS children with detectable P-sIgG4 levels and POIT but not from nonsensitized nonallergic children. Depletion of IgG4 from plasma of children with PS (and POIT) sensitized to Ara h 1 to Ara h 3 partially restored peanut-induced mast cell activation (P = .007).ConclusionsDifferences in sIgE levels and allergen specificity could not justify the clinical phenotype in all children with PA and PS children. Blocking IgG4 antibodies provide an additional explanation for the absence of clinical reactivity in PS patients sensitized to major peanut allergens.

Project description:BackgroundMast cells and basophils are key effector cells of IgE-mediated anaphylactic reactions. The Chinese herbal formula, food allergy herbal formula 2 (FAHF-2), protects against peanut anaphylaxis in mice. However, the mechanisms underlying this effect are not fully elucidated.ObjectiveTo investigate whether FAHF-2 inhibits mast cell/basophil numbers and IgE-mediated activation.MethodsMice with peanut allergy (PNA mice) were treated with FAHF-2 intragastrically for 7 weeks and challenged intragastrically with peanut 1 day and 4 weeks posttreatment. Peripheral blood basophil numbers and peritoneal mast cell numbers and FcεRI expression were determined. Direct effects of FAHF-2 on the murine mast cell line MC/9, and effects of 4 fractions and 3 compounds isolated from FAHF-2 on rat basophilic leukemia cells (RBL-2H3) and human skin mast cells degranulation and on the IgE-mediated spleen tyrosine kinase signaling pathway, were determined.ResultsAlthough all sham-treated PNA mice developed anaphylaxis, FAHF-2-treated PNA mice were protected against anaphylaxis after peanut challenge at 1 day and 4 weeks posttherapy. Reduction of peripheral blood basophils began after 1 week of treatment and continued for at least 4 weeks posttherapy. The number and FcεRI expression of peritoneal mast cells were also significantly decreased 4 weeks posttherapy. FAHF-2-treated MC/9 cells showed significantly reduced IgE-induced FcεRI expression, FcεRI γ mRNA subunit expression, proliferation, and histamine release on challenge. Fraction 2 from FAHF-2 inhibited RBL-2H3 cell and human mast cell degranulation. Three compounds from fraction 2-berberine, palmatine, and jatrorrhizine-inhibited RBL-2H3 cell degranulation via suppressing spleen tyrosine kinase phosphorylation.ConclusionFood allergy herbal formula 2 reduction of basophils and mast cell numbers as well as suppression of IgE-mediated mast cell activation may contribute to FAHF-2's persistent protection against peanut anaphylaxis.

Dataset Information

Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy.

Publications

Kinetics of mast cell, basophil, and oral food challenge responses in omalizumab-treated adults with peanut allergy.

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