P Engeroff1, F Caviezel1, F Storni1, F Thoms2, M Vogel1, M F Bachmann1,3. 1. Department of Rheumatology, Immunology and Allergology, University Hospital, University of Bern, Bern, Switzerland. 2. Department of Dermatology, Zurich University Hospital, Schlieren/Zurich, Switzerland. 3. Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, UK.
Abstract
BACKGROUND: The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased protective IgG responses compared to free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. METHODS: We differentiated human mast cells in vitro from blood-derived stem cell progenitors and sensitized the cells with a monoclonal Fel d 1-specific IgE. We compared the capability of Fel d 1 to induce mast cell activation in its free form versus displayed on VLPs and we performed allergen binding studies by surface plasmon resonance as well as flow cytometry. RESULTS: We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d 1 displayed on VLPs fails to induce mast cell activation. We demonstrate that this inability to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation. CONCLUSION: These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.
BACKGROUND: The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased protective IgG responses compared to free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. METHODS: We differentiated human mast cells in vitro from blood-derived stem cell progenitors and sensitized the cells with a monoclonal Fel d 1-specific IgE. We compared the capability of Fel d 1 to induce mast cell activation in its free form versus displayed on VLPs and we performed allergen binding studies by surface plasmon resonance as well as flow cytometry. RESULTS: We show that free Fel d 1 induces degranulation of IgE-sensitized mast cells whereas Fel d 1 displayed on VLPs fails to induce mast cell activation. We demonstrate that this inability to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation. CONCLUSION: These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.
Authors: Federico Storni; Gustavo Cabral-Miranda; Elisa Roesti; Lisha Zha; Paul Engeroff; Andris Zeltins; Mark Cragg; Monique Vogel; Martin F Bachmann Journal: Int Arch Allergy Immunol Date: 2020-03-10 Impact factor: 2.749
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