Background: Cow’s milk allergy (CMA) is an important problem worldwide and the development of an in vivo system to study new immunotherapeutic strategies is of interest. Intolerance to soybean formula has been described in CMA patients, but it is not fully understood. In this work, we used a food allergy model in BALB/c mice to study the cross-reactivity between cow’s milk protein (CMP) and soy proteins (SP). Methods: Mice were orally sensitized with cholera toxin and CMP, and then challenged with CMP or SP to induce allergy. Elicited symptoms, plasma histamine, humoral and cellular immune response were analyzed. Th1- and Th2-associated cytokines and transcription factors were assessed at mucosal sites and in splenocytes. Cutaneous tests were also performed. Results: We found that the immediate symptoms elicited in CMP-sensitized mice orally challenged with SP were consistent with a plasma histamine increase. The serum levels of CMP-specific IgE and IgG1 antibodies were increased. These antibodies also recognized soy proteins. Splenocytes and mesenteric lymph node cells incubated with CMP or SP secreted IL-5 and IL-13. mRNA expression of Th2-associated genes (IL-5, IL-13, and GATA-3) was upregulated in mucosal samples. In addition, sensitized animals exhibited positive cutaneous tests after the injection of CMP or SP. Conclusions: We demonstrate that CMP-sensitized mice, without previous exposure to soy proteins, elicited hypersensitivity signs immediately after the oral administration of SP, suggesting that the immunochemical cross-reactivity might be clinically relevant. This model may provide an approach to further characterize cross-allergenicity phenomena and develop new immunotherapeutic treatments for allergic patients.

Keywords:
Food allergy, Cow’s milk, Mouse model, Cross-reactivity, Soybean, Hypersensitivity
1.
Coombes JL, Powrie F: Dendritic cells in intestinal immune regulation. Nat Rev Immunol 2008;8:435–446.
2.
Tezuka H, Ohteki T: Regulation of intestinal homeostasis by dendritic cells, Immunol Rev 2010, pp 247–258.
3.
Cardoso CR, Provinciatto PR, Godoi DF, Vieira TS, Ferreira BR, Teixeira G, Rossi MA, Cunha FQ, Silva JS: B cells are involved in the modulation of pathogenic gut immune response in food-allergic enteropathy. Clin Exp Immunol 2008;154:153–161.
4.
Kitagawa S, Zhang S, Harari Y, Castro GA: Relative allergenicity of cow’s milk and cow’s milk-based formulas in an animal model. Am J Med Sci 1995;310:183–187.
5.
Li XM, Schofield BH, Huang CK, Kleiner GI, Sampson HA: A murine model of IgE-mediated cow’s milk hypersensitivity. J Allergy Clin Immunol 1999;103:206–214.
6.
Takayama N, Igarashi O, Kweon M-N, Kiyono H: Regulatory role of Peyer’s patches for the inhibition of OVA-induced allergic diarrhea. Clin Immunol 2007;123:199–208.
7.
Elson CO, Ealding W: Cholera toxin feeding did not induce oral tolerance in mice and abrogated oral tolerance to an unrelated protein antigen. J Immunol 1984;133:2892–2897.
8.
Ganeshan K, Neilsen CV, Hadsaitong A, Schleimer RP, Luo X, Bryce PJ: Impairing oral tolerance promotes allergy and anaphylaxis: a new murine food allergy model. J Allergy Clin Immunol 2009;123:231–238.
9.
Parvataneni S, Gonipeta B, Tempelman RJ, Gangur V: Development of an adjuvant-free cashew nut allergy mouse model. Int Arch Allergy Immunol 2009;149:299–304.
10.
Anderson LB Jr, Dreyfuss EM, Logan J, Johnstone DE, Glaser J: Melon and banana sensitivity coincident with ragweed pollinosis. J Allergy 1970;45:310–319.
11.
Valenta R, Duchene M, Ebner C, Valent P, Sillaber C, Deviller P, Ferreira F, Tejkl M, Edelmann H, Kraft D: Profilins constitute a novel family of functional plant pan-allergens. J Exp Med 1992;175:377–385.
12.
Hirschwehr R, Valenta R, Ebner C, Ferreira F, Sperr WR, Valent P, Rohac M, Rumpold H, Scheiner O, Kraft D: Identification of common allergenic structures in hazel pollen and hazelnuts: a possible explanation for sensitivity to hazelnuts in patients allergic to tree pollen. J Allergy Clin Immunol 1992;90:927–936.
13.
van Ree R: Clinical importance of cross-reactivity in food allergy. Curr Opin Allergy Clin Immunol 2004;4:235–240.
14.
Kulis M, Pons L, Burks AW: In vivo and T cell cross-reactivity between walnut, cashew and peanut. Int Arch Allergy Immunol 2009;148:109–117.
15.
Sampson HA: Food allergy. J Allergy Clin Immunol 1989;84:1062–1067.
16.
Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, Sigurdardottir ST, Lindner T, Goldhahn K, Dahlstrom J, McBride D, Madsen C: The prevalence of food allergy: a meta-analysis. J. Allergy Clin Immunol 2007;120:638–646.
17.
Branum AM, Lukacs SL: Food allergy among children in the United States. Pediatrics 2009;124:1549–1555.
18.
Terracciano L, Isoardi P, Arrigoni S, Zoja A, Martelli A: Use of hydrolysates in the treatment of cow’s milk allergy. Ann Allergy Asthma Immunol 2002;89:86–90.
19.
Zeiger RS, Sampson HA, Bock SA, Burks AW Jr, Harden K, Noone S, Martin D, Leung S, Wilson G: Soy allergy in infants and children with IgE-associated cow’s milk allergy. J Pediatr 1999;134:614–622.
20.
Zoppi G, Guandalini S: The story of soy formula feeding in infants: a road paved with good intentions. J Pediatr Gastroenterol Nutr 1999;28:541–543.
21.
Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R, Varjonen E: Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow’s milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr 2002;140:219–224.
22.
Ahn K-M, Han Y-S, Nam S-Y, Park H-Y, Shin M-Y, Lee S-I: Prevalence of soy protein hypersensitivity in cow’s milk protein-sensitive children in Korea. J Korean Med Sci 2003;18:473–477.
23.
Rozenfeld P, Docena GH, Añón MC, Fossati CA: Detection and identification of a soy protein component that cross-reacts with caseins from cow’s milk. Clin Exp Immunol 2002;130:49–58.
24.
Curciarello R, Lareu JF, Fossati CA, Docena GH, Petruccelli S: Immunochemical characterization of Glycine max L. Merr. var Raiden, as a possible hypoallergenic substitute for cow’s milk-allergic patients. Clin Exp Allergy 2008;38:1559–1565.
25.
Ceska M: Radioimmunoassay of IgE using paper disks. Meth Enzymol 1981;73:646–656.
26.
Mittag D, Vieths S, Vogel L, Becker W-M, Rihs H-P, Helbling A, Wüthrich B, Ballmer-Weber BK: Soybean allergy in patients allergic to birch pollen: clinical investigation and molecular characterization of allergens. J Allergy Clin Immunol 2004;113:148–154.
27.
Aalberse RC, Van Ree R: Monoclonal antibody assays for allergens: pick your antibodies with care! J Allergy Clin Immunol 2000;106:625–626.
28.
Ferreira F, Hawranek T, Gruber P, Wopfner N, Mari A: Allergic cross-reactivity: from gene to the clinic. Allergy 2004;59:243–267.
29.
Untersmayr E, Bakos N, Schöll I, Kundi M, Roth-Walter F, Szalai K, Riemer AB, Ankersmit HJ, Scheiner O, Boltz-Nitulescu G, Jensen-Jarolim E: Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients. FASEB J 2005;19:656–658.
30.
Schöll I, Untersmayr E, Bakos N, Roth-Walter F, Gleiss A, Boltz-Nitulescu G, Scheiner O, Jensen-Jarolim E: Antiulcer drugs promote oral sensitization and hypersensitivity to hazelnut allergens in BALB/c mice and humans. Am J Clin Nutr 2005;81:154–160.
31.
Brunner R, Wallmann J, Szalai K, Karagiannis P, Kopp T, Scheiner O, Jensen-Jarolim E, Pali-Schöll I: The impact of aluminium in acid-suppressing drugs on the immune response of BALB/c mice. Clin Exp Allergy 2007;37:1566–1573.
32.
Vandezande LM, Wallaert B, Desreumaux P, Tsicopoulos A, Lamblin C, Tonnel AB, Janin A: Interleukin-5 immunoreactivity and mRNA expression in gut mucosa from patients with food allergy. Clin Exp Allergy 1999;29:652–659.
33.
Beyer K, Castro R, Birnbaum A, Benkov K, Pittman N, Sampson HA: Human milk-specific mucosal lymphocytes of the gastrointestinal tract display a TH2 cytokine profile. J Allergy Clin Immunol 2002;109:707–713.
34.
Adel-Patient K, Bernard H, Ah-Leung S, Créminon C, Wal J: 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 2005;60:658–664.
35.
Pons L, Ponnappan U, Hall RA, Simpson P, Cockrell G, West CM, Sampson HA, Helm RM, Burks AW: Soy immunotherapy for peanut-allergic mice: modulation of the peanut-allergic response. J Allergy Clin Immunol 2004;114:915–921.
36.
Lifrani A, Dubarry M, Rautureau M, Aattouri N, Boyaka PN, Tomé D: Peanut-lupine antibody cross-reactivity is not associated to cross-allergenicity in peanut-sensitized mouse strains. Int Immunopharmacol 2005;5:1427–1435.
37.
Klemola T, Kalimo K, Poussa T, Juntunen-Backman K, Korpela R, Valovirta E, Vanto T: Feeding a soy formula to children with cow’s milk allergy: the development of immunoglobulin E-mediated allergy to soy and peanuts. Pediatr Allergy Immunol 2005;16:641–646.
38.
Lack G, Fox D, Northstone K, Golding J: Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977–985.
39.
von der Weid T, Bulliard C, Fritsché R: Suppression of specific and bystander IgE responses in a mouse model of oral sensitization to beta-lactoglobulin. Int Arch Allergy Immunol 2001;125:307–315.
40.
Bolhaar STHP, Tiemessen MM, Zuidmeer L, van Leeuwen A, Hoffmann-Sommergruber K, Bruijnzeel-Koomen CAFM, Taams LS, Knol EF, van Hoffen E, van Ree R, Knulst AC: Efficacy of birch-pollen immunotherapy on cross-reactive food allergy confirmed by skin tests and double-blind food challenges. Clin Exp Allergy 2004;34:761–769.
41.
Kinaciyan T, Jahn-Schmid B, Radakovics A, Zwölfer B, Schreiber C, Francis JN, Ebner C, Bohle B: Successful sublingual immunotherapy with birch pollen has limited effects on concomitant food allergy to apple and the immune response to the Bet v 1 homolog Mal d1. J Allergy Clin Immunol 2007;119:937–943.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.