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Evaluation of biotechnology-derived novel proteins for the risk of food-allergic potential: advances in the development of animal models and future challenges

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Abstract

Increasing concern from the public about the safety of genetically modified food has made critical to have suitable methods for recognizing associated potential hazards. Hierarchical approaches to allergenicity determination were proposed, and these include evaluation of the structural and sequence homology and serological identity of novel proteins with existing allergens, measuring the resistance to proteolytic digestion and assessment of sensitizing potential using animal models. Allergic individuals have a predisposed (i.e. atopic) genetic background, and a close resemblance to this setup is therefore desirable in animal models, which is possible by using a strain of an animal species that is prone for allergic disorders. So far, none of the animal model has been validated for the purpose of hazard identification in the context of safety assessment. However, the available knowledge suggests that the judicious use of an appropriate animal model could provide important information about the allergic potential of novel proteins. This paper provides an up-to-date review of the progress made in the field of development of in vivo models in this direction and the further goals that have to be achieved.

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References

  • Adel-Patient K, Creminon C, Bernard H, Clement G, Negroni L, Frobert Y, Grassi J, Wal JM, Chatel JM (2000) Evaluation of a high IgE-responder mouse model of allergy to bovine beta-lactoglobulin (BLG): development of sandwich immunoassays for total and allergen-specific IgE, IgG1 and IgG2a in BLG-sensitized mice. J Immunol Methods 235:21–32

    Article  CAS  PubMed  Google Scholar 

  • Adel-Patient K, Creminon C, Boquet D, Wal JM, Chatel JM (2001) Genetic immunisation with bovine beta-lactoglobulin cDNA induces a preventive and persistent inhibition of specific anti-BLG IgE response in mice. Int Arch Allergy Immunol 126:59–67

    Article  CAS  PubMed  Google Scholar 

  • Akiyama H, Teshima R, Sakushima JI, Okunuki H, Goda Y, Sawada JI, Toyoda M (2001) Examination of oral sensitization with ovalbumin in Brown Norway rats and three strains of mice. Immunol Lett 78:1–5

    Article  CAS  PubMed  Google Scholar 

  • Bailey M, Miller BG, Telemo E, Stokes CR, Bourne FJ (1993) Specific immunological unresponsiveness following active primary responses to proteins in the weaning diet of piglets. Int Arch Allergy Immunol 101:266–271

    Article  CAS  PubMed  Google Scholar 

  • Baker E (1990) Food allergy. In: Small animal allergy: a practical guide. Lea & Febiger, Philadelphia, pp 94–118

    Google Scholar 

  • Bashir ME, Louie S, Shi HN, Nagler-Anderson C (2004) Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy. J Immunol 172:6978–6987

    CAS  PubMed  Google Scholar 

  • Batista R, Saibo N, Lourencxo T (2008) Microarray analyses reveal that plant mutagenesis may induce more transcriptomic changes than transgene insertion. Proc Natl Acad Sci USA 105:3640–3645

    Article  CAS  PubMed  Google Scholar 

  • Berin MC, Zheng Y, Domaradzki M, Li XM, Sampson HA (2006) Role of TLR4 in allergic sensitization to food proteins in mice. Allergy 61:64–71

    Article  CAS  PubMed  Google Scholar 

  • Birmingham NP, Parvataneni S, Hassan HM, Harkema J, Samineni S, Navuluri L, Kelly CJ, Gangur V (2007) An adjuvant-free mouse model of tree nut allergy using hazelnut as a model tree nut. Int Arch Allergy Immunol 144:203–210

    Article  CAS  PubMed  Google Scholar 

  • Bock SA, Munoz-Furlong A, Sampson HA (2002) Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 107:191–193

    Article  Google Scholar 

  • Bodinier M, Leroy M, Ah-Leung S, Blanc F, Tranquet O, Denery-Papini S, Wal JM, Adel-Patient K (2009) Sensitization and elicitation of an allergic reaction to wheat gliadins in mice. J Agric Food Chem 57:1219–1225

    Article  CAS  PubMed  Google Scholar 

  • Bowman CC, Selgrade MK (2008a) Differences in allergenic potential of food extracts following oral exposure in mice reflect differences in digestibility: Potential approaches to safety assessment. Toxicol Sci 102:100–109

    Article  CAS  PubMed  Google Scholar 

  • Bowman CC, Selgrade MK (2008b) Failure to induce oral tolerance in mice is predictive of dietary allergenic potency among foods with sensitizing capacity. Toxicol Sci 106:435–443

    Article  CAS  PubMed  Google Scholar 

  • Bowman CC, Selgrade MK (2009) Utility of rodent models for evaluating protein allergenicity. Regul Toxicol Pharmacol 54(Suppl 3):S58–61

    Google Scholar 

  • Buchanan BB, Frick OL (2002) The dog as a model for food allergy. Ann N Y Acad Sci 964:173–183

    Article  CAS  PubMed  Google Scholar 

  • Burks AW, Sampson HA (1997) Anaphylaxis and food allergy. In: Metcalfe DD, Sampson HA, Simon RA (eds) Food allergy: adverse reactions to foods and food additives. Blackwell Science, Cambridge, MA, pp 25–245

    Google Scholar 

  • Christensen HR, Kjaer TM, Frokiaer H (2003) Low-dose oral tolerance due to antigen in the diet suppresses differentially the cholera toxin-adjuvantized IgE, IgA and IgG response. Int Arch Allergy Immunol 132:248–257

    Article  CAS  PubMed  Google Scholar 

  • Codex Alimentarius Commission (2003) Alinorm 03/34: joint FAO/WHO Food Standard Programme, Codex Alimentarius Commission, twenty-fifth sessions, Rome, Italy, 30 June–5 July, 2003. Appendix III, guideline for the conduct of food safety assessment of foods derived from recombinant-DNA plants, and appendix IV, annex on the assessment of possible allergenicity, pp 47–60. http://www.codexalimentarius.net/download/report/116/al03_13e.pdf

  • Dearman RJ, Kimber I (2007) A mouse model for food allergy using intraperitoneal sensitization. Methods 41:91–98

    Article  CAS  PubMed  Google Scholar 

  • Dearman RJ, Caddick H, Stone S, Basketter DA, Kimber I (2001) Characterization of antibody responses induced in rodents by exposure to food proteins: influence of route of exposure. Toxicology 167:217–231

    Article  CAS  PubMed  Google Scholar 

  • Dearman RJ, Caddick H, Stone S, Kenna JG, Basketter DA, Kimber I (2002) Immunogenic properties of rapidly digested food proteins following gavage exposure of mice: a comparison of ovalbumin with a potato acid phosphatase preparation. Food Chem Toxicol 40:625–633

    Article  CAS  PubMed  Google Scholar 

  • Desvignes C, Bour H, Nicolas JF, Kaiserlian D (1996) Lack of oral tolerance but oral priming for contact sensitivity to dinitrofluorobenzene in major histocompatibility complex class II deficient mice and in CD4 + T cell-depleted mice. Eur J Immunol 26:1756–1761

    Article  CAS  PubMed  Google Scholar 

  • Desvignes C, Esteves F, Etchart N, Bella C, Czerkinsky C, Kaiserlian D (1998) The murine buccal mucosa is an inductive site for priming class I-restricted CD8 + effector T cells in vivo. Clin Exp Immunol 113:386–393

    Article  CAS  PubMed  Google Scholar 

  • Desvignes C, Etchart N, Kehren J, Akiba I, Nicolas JF, Kaiserlian D (2000) Oral administration of hapten inhibits in vivo induction of specific cytotoxic CD8 + T cells mediating tissue inflammation: a role for regulatory CD4 + T cells. J Immunol 164:2515–2522

    CAS  PubMed  Google Scholar 

  • Dubois B, Chapat L, Goubier A, Kaiserlian D (2003) CD4 + CD25 + T cells as key regulators of immune responses. Eur J Dermatol 13:111–116

    PubMed  Google Scholar 

  • Ermel RW, Kock M, Griffey SM, Reinhart GA, Frick OL (1997) The atopic dog: a model for food allergy. Lab Anim Sci 47:40–49

    CAS  PubMed  Google Scholar 

  • European Food Safety Authority (EFSA) (2006) Guidance document for the risk assessment of genetically modified plants and derived food and feed by the Scientific Panel on Genetically Modified Organisms (GMO). The EFSA J 99:1–100

    Google Scholar 

  • FAO/WHO (2001) Evaluation of allergenicity of genetically modified foods. Report of a joint FAO/WHO expert consultation on allergenicity of foods derived from biotechnology, Rome, Italy. Available at: http://www.who.int/foodsafety/publications/biotech/en/ec_jan2001.pdf

  • Fritsche R (2003) Animal models in food allergy: assessment of allergenicity and preventive activity of infant formulas. Toxicol Lett 140–141:303–309

    Article  PubMed  Google Scholar 

  • Frossard CP, Hauser C, Eigenmann PA (2004a) Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy. J Allergy Clin Immunol 114:377–382

    Article  CAS  PubMed  Google Scholar 

  • Frossard CP, Tropia L, Hauser C, Eigenmann PA (2004b) Lymphocytes in Peyer patches regulate clinical tolerance in a murine model of food allergy. J Allergy Clin Immunol 113:958–964

    Article  CAS  PubMed  Google Scholar 

  • 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 123:231–238

    Article  CAS  PubMed  Google Scholar 

  • Gizzarelli F, Corinti S, Barletta B, Iacovacci P, Brunetto B, Butteroni C, Afferni C, Onori R, Miraglia M, Panzini G, Di Felice G, Tinghino R (2006) Evaluation of allergenicity of genetically modified soybean protein extract in a murine model of oral allergen-specific sensitization. Clin Exp Allergy 36:238–248

    Article  CAS  PubMed  Google Scholar 

  • Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, Trinchieri G, Kaiserlian D (2008) Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29:464–1375

    Article  CAS  PubMed  Google Scholar 

  • Griffiths CEM, Dearman RJ, Cumberbatch M, Kimber I (2005) Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine 32:67–70

    Article  CAS  PubMed  Google Scholar 

  • Halliwell REW (1992) Management of dietary hypersensitivity in the dog. J Small Anim Pract 33:156–160

    Article  Google Scholar 

  • Hankins CC, Noland PR, Burks AW Jr, Connaughton C, Cockrell G, Metz CL (1992) Effect of soy protein ingestion on total and specific immunoglobulin G concentrations in neonatal porcine serum measured by enzyme-linked immunosorbent assay. J Anim Sci 70:3096–3101

    CAS  PubMed  Google Scholar 

  • Hausding M, Sauer K, Maxeiner JH, Finotto S (2008) Transgenic models in allergic responses. Curr Drug Targets 9:503–510

    Article  CAS  PubMed  Google Scholar 

  • Hefle SL, Nordlee JA, Taylor SL (1996) Allergenic foods. Crit Rev Food Sci Nutr 36:S69–S89

    Article  CAS  PubMed  Google Scholar 

  • Helm RM, Burks AW (2000) Mechanisms of food allergy. Curr Opin Immunol 12:647–653

    Article  CAS  PubMed  Google Scholar 

  • Helm RM, Furuta GT, Stanley JS et al (2002) A neonatal swine model for peanut allergy. J Allergy Clin Immunol 109:136–142

    Article  PubMed  Google Scholar 

  • Helm RM, Ermel RW, Frick OL (2003) Nonmurine animal models of food allergy. Environ Health Perspect 111:239–244

    Article  PubMed  Google Scholar 

  • Hilton J, Dearman RJ, Sattar N, Basketter DA, Kimber I (1997) Characteristics of antibody responses induced in mice by protein allergens. Food Chem Toxicol 35:1209–1218

    Article  CAS  PubMed  Google Scholar 

  • Holt PG, Macaubas C, Prescott SL, Sly PD (2000) Primary sensitization to inhalant allergens. Am J Respir Crit Care Med 162:S91–S94

    CAS  PubMed  Google Scholar 

  • Jeffers JG, Shanley KJ, Meyer EK (1991) Diagnostic testing of dogs for food hypersensitivity. J Am Vet Med Assoc 198:245–250

    CAS  PubMed  Google Scholar 

  • Kaiserlian D, Cerf-Bensussan N, Hosmalin A (2005) The mucosal immune system: from control of inflammation to protection against infections. J Leukoc Biol 78:311–318

    Article  CAS  PubMed  Google Scholar 

  • Kemeny DM (1994) Proceedings, conference on scientific issues related to potential allergenicity in transgenic food crops. FDA docket no. 94N-0053. FDA, Food and Drug Administration, Washington, DC

  • Kitagawa S, Zhang S, Harari Y, Castro GA (1995) Relative allergenicity of cow’s milk and cow’s milk-based formulas in an animal model. Am J Med Sci 310:183–187

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, Penninks AH (2003) Assessment of the allergic potential of food protein extracts and proteins on oral application using the brown Norway rat model. Environ Health Perspect 111:233–238

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, Penninks AH, Houben GF (1998a) Continued expression of anti-soy protein antibodies in rats bred on a soy protein-free diet for one generation: the importance of dietary control in oral sensitization research. J Allergy Clin Immunol 101:815–820

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, Penninks AH, Spanhaak S, Houben GF (1998b) Oral sensitization to food proteins: a brown Norway rat model. Clin Exp Allergy 28:368–375

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, Penninks AH, Smit JJ, Houben GF (1999a) Immune-mediated effects upon oral challenge of ovalbumin-sensitized Brown Norway rats: further characterization of a rat food allergy model. Toxicol Appl Pharmacol 156:161–169

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, Penninks AH, van Meeteren M, Houben GF (1999b) Humoral and cellular immune responses in different rat strains on oral exposure to ovalbumin. Food Chem Toxicol 37:881–888

    Article  CAS  PubMed  Google Scholar 

  • Knippels LM, van der Kleij HP, Koppelman SJ, Houben GF, Penninks AH (2000) Comparison of antibody responses to hen’s egg and cow’s milk proteins in orally sensitized rats and food-allergic patients. Allergy 55:251–258

    Article  CAS  PubMed  Google Scholar 

  • 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 103:206–214

    Article  CAS  PubMed  Google Scholar 

  • 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 106:150–158

    Article  CAS  PubMed  Google Scholar 

  • Metcalfe DD, Astwood JD, Townsend R, Sampson HA, Taylor SL, Fuchs RL (1996) Assessment of the allergenic potential of foods derived from genetically engineered crop plants. Crit Rev Food Sci Nutr 36:S165–S186

    Article  CAS  PubMed  Google Scholar 

  • Morafo V, Srivastava K, Huang CK, Kleiner G, Lee SY, Sampson HA, Li AM (2003) Genetic susceptibility to food allergy is linked to differential Th1-Th2 responses in C3H-HeJ and BALB/c mice. J Allergy Clin Immunol 111:1122–1128

    Article  CAS  PubMed  Google Scholar 

  • NIH (2006) Report of the NIH expert panel on food allergy research. March 13–14, 2006, National Institute of Allergy and Infectious Diseases, National Institute of Health. Available at: http://www3.niaid.nih.gov/news/newsreleases/2007/FoodAllergyExpertPanel.htm

  • Pilegaard K, Madsen C (2004) An oral Brown Norway rat model for food allergy: comparison of age, sex, dosing volume, and allergen preparation. Toxicology 196:247–257

    Article  CAS  PubMed  Google Scholar 

  • Prescott VE, Hogan SP (2006) Genetically modified plants and food hypersensitivity diseases: usage and implications of experimental models for risk assessment. Pharmacol Ther 111:374–383

    Article  CAS  PubMed  Google Scholar 

  • Rupa P, Hamilton K, Cirinna M, Wilkie BN (2008) A neonatal swine model of allergy induced by the major food allergen chicken ovomucoid (Gal d 1). Int Arch Allergy Immunol 146:11–18

    Article  CAS  PubMed  Google Scholar 

  • Saklayen MG, Pesce AJ, Pollak VE, Michael JG (1984) Kinetics of oral tolerance. Study of variables affecting tolerance induced by oral administration of antigen. Int Arch Allergy Appl Immunol 73:5–9

    Article  CAS  PubMed  Google Scholar 

  • Sampson HA, McCaskill CC (1985) Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 107:669–675

    Article  CAS  PubMed  Google Scholar 

  • Sicherer SH, Sampson HA (2006) Food allergy. J Allergy Clin Immunol 117:S470–S475

    Article  CAS  PubMed  Google Scholar 

  • Strid J, Thomson M, Hourihane J, Kimber I, Strobel S (2004) A novel model of sensitization and oral tolerance to peanut protein. Immunology 113:293–303

    Article  CAS  PubMed  Google Scholar 

  • Strid J, Hourihane J, Kimber I, Callard R, Strobel S (2005) Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin Exp Allergy 35:757–766

    Article  CAS  PubMed  Google Scholar 

  • Strobel S, Mowat AM (2006) Oral tolerance and allergic responses to food proteins. Curr Opin Allergy Clin Immunol 6:207–213

    Article  CAS  PubMed  Google Scholar 

  • Teuber SS, Del Val G, Morigasaki S, Jung HR, Eisele PH, Frick OL, Buchanan BB (2002) The atopic dog as a model of peanut and tree nut food allergy. J Allergy Clin Immunol 110:921–927

    Article  PubMed  Google Scholar 

  • Vaz NM, Vaz EM, Levine BB (1970) Relationship between H-2 genotype and immune responsiveness to low doses of ovalbumin in the mouse. J Immunol 104:1572–1574

    CAS  PubMed  Google Scholar 

  • Vaz NM, Phillips-Quagliata JM, Levine BB, Vaz EM (1971) H-2 linked genetic control of immune responsiveness to ovalbumin and ovamucoid. J Exp Med 134:1335–1348

    Article  CAS  PubMed  Google Scholar 

  • Yamanishi R, Yusa I, Bando N, Terao J (2003) Adjuvant activity of alum in inducing antigen specific IgE antibodies in BALB/c mice: a reevaluation. Biosci Biotechnol Biochem 67:166–169

    Article  CAS  PubMed  Google Scholar 

  • Yocum MW, Butterfield JH, Klein JS et al (1999) Epidemiology of anaphylaxis in Olmsted County: a population-based study. J Allergy Clin Immunol 104:452–456

    Article  CAS  PubMed  Google Scholar 

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Ahuja, V., Quatchadze, M., Ahuja, V. et al. Evaluation of biotechnology-derived novel proteins for the risk of food-allergic potential: advances in the development of animal models and future challenges. Arch Toxicol 84, 909–917 (2010). https://doi.org/10.1007/s00204-010-0582-0

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