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Induction of Hypersensitivity with Purified Beta-Lactoglobulin as a Mouse Model of Cow’s Milk Allergy

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Animal Models of Allergic Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2223))

Abstract

Cow’s milk allergy is one of the most prevalent food allergies in both children and adults. As dairy products are common dietary ingredients and the prevalence of chronic conditions is on the rise, milk allergy is a growing public health concern. To elucidate underlying mechanisms and develop therapeutic strategies, reliable animal models are essential research tools. Sensitization to a milk protein is the principal procedure for establishing animal models of cow’s milk allergy. However, the methods of sensitization vary from laboratory to laboratory, using different milk proteins with different amounts, routes, and durations of allergen exposure during sensitization of varying sex and strains of mice, likely resulting in diverse immunological and physical responses. Furthermore, the sources and potential impurities of milk protein may also produce variable responses. Thus, standardization of sensitization protocol is important, particularly when results are compared across studies. Here, we describe a method to generate a mouse model of cow’s milk allergy using purified β-lactoglobulin as the milk allergen with cholera toxin as an adjuvant in a 5-week oral sensitization protocol.

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References

  1. Gupta RS, Warren CM, Smith BM, Blumenstock JA, Jiang J, Davis MM, Nadeau KC (2018) The public health impact of parent-reported childhood food allergies in the United States. Pediatrics December 2018, 142(6):e20181235. https://doi.org/10.1542/peds.2018-1235

  2. Gupta RS, Warren CM, Smith BM, Jiang J, Blumenstock JA, Davis MM, Schleimer RP, Nadeau KC (2019) Prevalence and severity of food allergies among US adults. JAMA Netw Open 2(1):e185630. https://doi.org/10.1001/jamanetworkopen.2018.5630

  3. Gupta R, Holdford D, Bilaver L, Dyer A, Holl JL, Meltzer D (2013) The economic impact of childhood food allergy in the United States. JAMA Pediatr 167(11):1026–1031. https://doi.org/10.1001/jamapediatrics.2013.2376

  4. Miller GF, Coffield E, Leroy Z, Wallin R (2016) Prevalence and costs of five chronic conditions in children. J Sch Nurs 32(5):357–364. https://doi.org/10.1177/1059840516641190

    Article  PubMed  PubMed Central  Google Scholar 

  5. Acker WW, Plasek JM, Blumenthal KG, Lai KH, Topaz M, Seger DL, Goss FR, Slight SP, Bates DW, Zhou L (2017) Prevalence of food allergies and intolerances documented in electronic health records. J Allergy Clin Immunol 140(6):1581–1591. https://doi.org/10.1016/j.jaci.2017.04.006

    Article  Google Scholar 

  6. Willits EK, Park MA, Hartz MF, Schleck CD, Weaver AL, Joshi AY (2018) Food allergy: a comprehensive population-based cohort study. Mayo Clin Proc 93(10):1423–1430. https://doi.org/10.1016/j.mayocp.2018.05.031

    Article  PubMed  PubMed Central  Google Scholar 

  7. Berin MC, Zheng Y, Domaradzki M, Li XM, Sampson HA (2006) Role of TLR4 in allergic sensitization to food proteins in mice. Allergy 61(1):64–71. https://doi.org/10.1111/j.1398-9995.2006.01012.x

    Article  CAS  PubMed  Google Scholar 

  8. de Theije CG, Wu J, Koelink PJ, Korte-Bouws GA, Borre Y, Kas MJ, Lopes da Silva S, Korte SM, Olivier B, Garssen J, Kraneveld AD (2014) Autistic-like behavioural and neurochemical changes in a mouse model of food allergy. Behav Brain Res 261:265–274. https://doi.org/10.1016/j.bbr.2013.12.008

    Article  CAS  PubMed  Google Scholar 

  9. Germundson DL, Smith NA, Vendsel LP, Kelsch AV, Combs CK, Nagamoto-Combs K (2018) Oral sensitization to whey proteins induces age- and sex-dependent behavioral abnormality and neuroinflammatory responses in a mouse model of food allergy: a potential role of mast cells. J Neuroinflammation 15(1):120. https://doi.org/10.1186/s12974-018-1146-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li XM, Serebrisky D, Lee SY, Huang CK, Bardina L, Schofield BH, Stanley JS, Burks AW, Bannon GA, Sampson HA (2000) A murine model of peanut anaphylaxis: T- and B-cell responses to a major peanut allergen mimic human responses. J Allergy Clin Immunol 106(1 Pt 1):150–158. https://doi.org/10.1067/mai.2000.107395

    Article  CAS  PubMed  Google Scholar 

  11. Smit JJ, Willemsen K, Hassing I, Fiechter D, Storm G, van Bloois L, Leusen JH, Pennings M, Zaiss D, Pieters RH (2011) Contribution of classic and alternative effector pathways in peanut-induced anaphylactic responses. PLoS One 6(12):e28917. https://doi.org/10.1371/journal.pone.0028917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smith NA, Germundson DL, Combs CK, Vendsel LP, Nagamoto-Combs K (2019) Astrogliosis associated with behavioral abnormality in a non-anaphylactic mouse model of cow’s milk allergy. Front Cell Neurosci 13:320. https://doi.org/10.3389/fncel.2019.00320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vonk MM, Wagenaar L, Pieters RHH, Knippels LMJ, Willemsen LEM, Smit JJ, van Esch B, Garssen J (2017) The efficacy of oral and subcutaneous antigen-specific immunotherapy in murine cow’s milk- and peanut allergy models. Clin Transl Allergy 7:35. https://doi.org/10.1186/s13601-017-0170-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ahrens R, Osterfeld H, Wu D, Chen CY, Arumugam M, Groschwitz K, Strait R, Wang YH, Finkelman FD, Hogan SP (2012) Intestinal mast cell levels control severity of oral antigen-induced anaphylaxis in mice. Am J Pathol 180(4):1535–1546. https://doi.org/10.1016/j.ajpath.2011.12.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marco-Martin G, La Rotta HA, Vazquez de la Torre M, Higaki Y, Zubeldia JM, Baeza ML (2017) Differences in the anaphylactic response between C3H/HeOuJ and BALB/c mice. Int Arch Allergy Immunol 173(4):204–212. https://doi.org/10.1159/000478983

    Article  CAS  PubMed  Google Scholar 

  16. Platzer B, Stout M, Fiebiger E (2015) Functions of dendritic-cell-bound IgE in allergy. Mol Immunol 68(2 Pt A):116–119. https://doi.org/10.1016/j.molimm.2015.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Snider DP, Marshall JS, Perdue MH, Liang H (1994) Production of IgE antibody and allergic sensitization of intestinal and peripheral tissues after oral immunization with protein Ag and cholera toxin. J Immunol (Baltimore, MD: 1950) 153(2):647–657

    CAS  Google Scholar 

  18. Ganeshan K, Neilsen CV, Hadsaitong A, Schleimer RP, Luo X, Bryce PJ (2009) Impairing oral tolerance promotes allergy and anaphylaxis: a new murine food allergy model. J Allergy Clin Immunol 123(1):231–238. https://doi.org/10.1016/j.jaci.2008.10.011

    Article  CAS  PubMed  Google Scholar 

  19. Galand C, Leyva-Castillo JM, Yoon J, Han A, Lee MS, McKenzie ANJ, Stassen M, Oyoshi MK, Finkelman FD, Geha RS (2016) IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells. J Allergy Clin Immunol 138(5):1356–1366. https://doi.org/10.1016/j.jaci.2016.03.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Proust B, Astier C, Jacquenet S, Ogier V, Magueur E, Roitel O, Belcourt C, Morisset M, Moneret-Vautrin DA, Bihain BE, Kanny G (2008) A single oral sensitization to peanut without adjuvant leads to anaphylaxis in mice. Int Arch Allergy Immunol 146(3):212–218. https://doi.org/10.1159/000115889

    Article  CAS  PubMed  Google Scholar 

  21. Venturelli N, Lexmond WS, Ohsaki A, Nurko S, Karasuyama H, Fiebiger E, Oyoshi MK (2016) Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33-basophil axis in mice. J Allergy Clin Immunol 138(5):1365–1380. https://doi.org/10.1016/j.jaci.2016.02.034

    Article  CAS  Google Scholar 

  22. Arumugam M, Ahrens R, Osterfeld H, Kottyan LC, Shang X, Maclennan JA, Zimmermann N, Zheng Y, Finkelman FD, Hogan SP (2011) Increased susceptibility of 129SvEvBrd mice to IgE-Mast cell mediated anaphylaxis. BMC Immunol 12:14. https://doi.org/10.1186/1471-2172-12-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wagenaar L, Bol-Schoenmakers M, Giustarini G, Garssen J, Smit JJ, Pieters RHH (2019) Mouse strain differences in response to oral immunotherapy for peanut allergy. Immun Inflamm Dis 7(1):41–51. https://doi.org/10.1002/iid3.242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adel-Patient K, Bernard H, Ah-Leung S, Creminon C, Wal JM (2005) Peanut- and cow’s milk-specific IgE, Th2 cells and local anaphylactic reaction are induced in Balb/c mice orally sensitized with cholera toxin. Allergy 60(5):658–664. https://doi.org/10.1111/j.1398-9995.2005.00767.x

    Article  CAS  PubMed  Google Scholar 

  25. Li XM, Schofield BH, Huang CK, Kleiner GI, Sampson HA (1999) A murine model of IgE-mediated cow’s milk hypersensitivity. J Allergy Clin Immunol 103(2 Pt 1):206–214

    Article  CAS  Google Scholar 

  26. Schouten B, van Esch BC, Hofman GA, van den Elsen LW, Willemsen LE, Garssen J (2008) Acute allergic skin reactions and intestinal contractility changes in mice orally sensitized against casein or whey. Int Arch Allergy Immunol 147(2):125–134. https://doi.org/10.1159/000135699

    Article  CAS  PubMed  Google Scholar 

  27. Horn CC, Kimball BA, Wang H, Kaus J, Dienel S, Nagy A, Gathright GR, Yates BJ, Andrews PL (2013) Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS One 8(4):e60537. https://doi.org/10.1371/journal.pone.0060537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Balbino B, Sibilano R, Starkl P, Marichal T, Gaudenzio N, Karasuyama H, Bruhns P, Tsai M, Reber LL, Galli SJ (2017) Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. J Allergy Clin Immunol 139(2):584–596. e510. https://doi.org/10.1016/j.jaci.2016.05.047

    Article  CAS  PubMed  Google Scholar 

  29. Makabe-Kobayashi Y, Hori Y, Adachi T, Ishigaki-Suzuki S, Kikuchi Y, Kagaya Y, Shirato K, Nagy A, Ujike A, Takai T, Watanabe T, Ohtsu H (2002) The control effect of histamine on body temperature and respiratory function in IgE-dependent systemic anaphylaxis. J Allergy Clin Immunol 110(2):298–303. https://doi.org/10.1067/mai.2002.125977

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM103442 and P20GM113123. Authors would like to thank Danielle Germundson at the University of North Dakota (UND) Department of Pathology and Brenda Kezar at UND Center for Biomedical Research.

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Correspondence to Kumi Nagamoto-Combs .

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Smith, N.A., Nagamoto-Combs, K. (2021). Induction of Hypersensitivity with Purified Beta-Lactoglobulin as a Mouse Model of Cow’s Milk Allergy. In: Nagamoto-Combs, K. (eds) Animal Models of Allergic Disease. Methods in Molecular Biology, vol 2223. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1001-5_5

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  • DOI: https://doi.org/10.1007/978-1-0716-1001-5_5

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1000-8

  • Online ISBN: 978-1-0716-1001-5

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