Bovine β-lactoglobulin-induced passive systemic anaphylaxis model using humanized NOG hIL-3/hGM-CSF transgenic mice

Abstract

Food allergy is a common disease caused by the intake of allergen-containing foods, such as milk, eggs, peanuts, and wheat. Systemic anaphylaxis is a severe hypersensitive allergic reaction resulting from degranulation of mast cells or basophils after crosslinking of surface high affinity IgE receptors (Fcε-RI) with allergen-specific IgE and allergens. In this study, we developed a novel human mast cell/basophil-engrafted mouse model that recapitulates systemic anaphylaxis triggered by β-lactoglobulin (BLG), the major allergen found in milk. Human CD34 + hematopoietic stem cells were transferred into NOG (non-Tg) or NOG hIL-3/hGM-CSF transgenic (Tg) mice. After 14–16 weeks, bovine BLG-specific human IgE was intravenously injected into the humanized mice, followed by intravenous or oral bovine BLG exposure 1 day later. Body temperature in Tg, but not in non-Tg, mice gradually decreased within 10 minutes, and 80% of Tg mice died within 1 hour by intravenous BLG exposure. Serum histamine levels and anaphylaxis scores in Tg mice were markedly increased compared to non-Tg mice. Furthermore, these allergic symptoms were significantly inhibited by epinephrine treatment into the Tg mice. Therefore, the current NOG hIL-3/hGM-CSF Tg mouse model may be useful for development of novel anaphylaxis drugs for the treatment of food allergies and for safety assessment of low-allergenicity extensively hydrolyzed cow’s milk whey protein-based infant formulas.

Animal Models for the Study of Food Allergies

“…Mediators and metabolites levels (Arumugam et al, 2011;Brandt et al, 2003;Burggraf et al, 2011;Burton et al, 2017;Feehley et al, 2019;Ito et al, 2021;Lexmond et al, 2016;Moutsoglou & Dreskin, 2016;Utsch et al, 2017;Yamani et al, 2018) Transcriptomics Transcriptome (Burton et al, 2018) Cell flow cytometry Phenotype, cellular composition, CD49b/IgE, CD200R, CD3, CD19, c-kit/IgE, CD107a, etc. (Hogan et al, 2000;Leonard et al, 2012;Lexmond et al, 2016;Lexmond et al, 2017)…”

“…Humanized mouse models generated by engrafting human cells or tissues into immunodeficient mice (Walsh et al., 2017) are predominantly created by injecting human PBMCs or HSCs from healthy or allergic donors into SCID mice (Burton et al., 2018; Burton et al., 2017; Hardy et al., 2022; Parvataneni et al., 2015; Wang et al., 2022; Weigmann et al., 2012) (Table 5). The SCID mice lack B and T cells and, in some cases, have been crossed with tg and KO mice (Ito et al., 2021). The advantage of humanized mice is that they provide an opportunity to study an in vivo human immune system.…”

“…Temperature (Ahrens et al, 2012;Branum & Lukacs, 2009;Hardy et al, 2022;Ito et al, 2021;Lexmond et al, 2016;Proust et al, 2008;Rodriguez et al, 2017;Smeekens & Kulis, 2021;Sun et al, 2007;Tanaka et al, 2011;Utsch et al, 2017;Yamani et al, 2021) Anaphylaxis i.v. Evan's blue followed by an allergen challenge Blue color in the extremities (Balbino et al, 2017;Inagaki, Miura, Nagai, & Koda, 1992;Makabe-Kobayashi et al, 2002;Ogino, Sakazaki Titers, gel electrophoresis, immunoblots, IgE binding epitope mapping (Arumugam et al, 2011;Brandt et al, 2003;Burton et al, 2017;Hardy et al, 2022;Hogan et al, 2000;Lexmond et al, 2016;…”

“…Cytokine expression (Ito et al, 2021;Lexmond et al, 2016) Mediators: mast cell proteases, histamine, tryptase, metabolites…”