Bortezomib treatment diminishes hazelnut‐induced intestinal anaphylaxis in mice

Abstract

Food allergy is a common health problem and can cause anaphylaxis. Avoidance of the offending food allergen is still the mainstay therapeutic approach. In this study, we investigated the role of plasma cell reduction by proteasome inhibition in a murine model of food allergy and examined the impact of this treatment on the systemic and local immune response. For this purpose, intestinal anaphylaxis was induced in BALB/c mice with the food allergen hazelnut, in conjunction with different adjuvants (alum and Staphylococcal enterotoxin B SEB) and different administration routes (oral and intraperitoneal). In both models, allergy symptoms were observed, but the clinical severity was more pronounced in the hazelnut-alum model than in the hazelnut-SEB model. Accordingly, allergen-specific immunoglobulin E (IgE) against hazelnut was detectable, and mast cell protease-1 in serum was increased after allergen provocation. Treatment with the proteasome inhibitor bortezomib reduced plasma cells and resulted in an abolishment of hazelnut allergen-specific IgE, which was associated with amelioration of clinical symptoms as well as a significant decrease in both CD19 + and follicular B lymphocytes. Our data demonstrate the importance of allergen-specific IgE in food allergy and point to B cells as potential therapeutic targets for its treatment. Keywords: Anaphylaxis B cells Food allergy Immunoglobulin E Proteasome inhibitionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAllergic reactions to food are common, and in most cases are caused by type 1-mediated hypersensitivity reactions [1]. Severe cases of food allergy may result in anaphylaxis, which can be fatal [1,2]. Features of food allergy include sensitization paramCorrespondence: Univ. Prof. Dr. med. Margitta Worm e-mail: margitta.worm@charite.de eters, such as the presence of allergen-specific immunoglobulin E (IgE), and typical clinical symptoms. These frequently consist of skin symptoms, such as urticaria and/or angioedema, but also include variable systemic responses, such as respiratory and cardiovascular symptoms [1][2][3]. Until now, the primary therapeutic approach for patients with food allergy has been strict avoidance of the offending food allergen [1]. Hazelnut (Corylus avellana) is a common cause of food allergy in Europe [4][5][6][7], and affects 0.1-0.5% of the population [8]. Hazelnut-allergic Eur. J. Immunol. 2016. 46: 1727-1736 a risk of severe or even fatal reactions [4][5][6]. Although sublingual immunotherapy and/or oral tolerance-induction has recently been shown to be effective for the treatment of peanut-allergic patients [9,10], their use in clinical practice is limited and currently restricted to specialized centers because of the risk of severe side effects. Another therapeutic approach to treat food allergy is the depletion of IgE. Indeed, the efficacy of an anti-IgE treatment has been demonstrated in patients suffering from food allergy [11]. Likewise, the anti-Ig...

Lifelong memory responses perpetuate humoral T H 2 immunity and anaphylaxis in food allergy

“…There is a dearth of knowledge regarding the essential events for the maintenance of Th2 humoral immunity to allergens. While targeting IgE + PCs has been proposed as a potential cure of food allergy 18,60 , our data show that IgE-mediated clinical reactivity to food allergens is not sustained by BM resident Ag-specific IgE + PCs. Instead, long-lived mucosal and systemic allergen-specific memory B cells, critically assisted by IL-4-producing CD4 T cells, replenish the allergen-specific IgE + PC compartment upon allergen exposure.…”

Non-classical B Cell Memory of Allergic IgE Responses

“…Treatment with the proteasome inhibitor bortezomib to deplete IgE plasma cells has provided more ambiguous results, in one case reducing circulating IgE and plasma cells but not allergy (102), and in another two studies, reducing IgE and suppressing allergic reactivity (103, 104). The variable results described in studies targeting plasma cells with bortezomib could be due to different sensitivities of plasma cells populations, and to an effect of plasma cells rebounding after plasma cell depletion (105).…”

Outstanding animal studies in allergy I. From asthma to food allergy and anaphylaxis

“…In another model hazelnut was applied orally and intraperitoneally. Usage of the Th2-adjuvant aluminium hydroxide (alum) led to stronger anaphylactic responses than using Staphylococcal enterotoxin B as adjuvant, which could in fact be therapeutically addressed by proteasome inhibitor bortezomib, reducing IgE and the B-cellular arm [61]. The question of the participation of IgG in the observed reactions was not addressed in this model.…”