Allergy Asthma Immunol Res.  2009 Oct;1(1):19-29. 10.4168/aair.2009.1.1.19.

Food allergy: recent advances in pathophysiology and treatment

• Wang J
• Sampson HA

• KMID: 2133795
• DOI: http://doi.org/10.4168/aair.2009.1.1.19

Abstract

Food allergies are adverse immune reactions to food proteins that affect up to 6% of children and 3-4% of adults. A wide range of symptoms can occur depending on whether IgE or non-IgE mediated mechanism are involved. Many factors influence the development of oral tolerance, including route of exposure, genetics, age of the host, and allergen factors. Advances have been made in the understanding of how these factors interact in the pathophysiology of food allergy. Currently, the mainstay of treatment for food allergies is avoidance and ready access to emergency medications. However, with the improved understanding of tolerance and advances in characterization of food allergens, several therapeutic strategies have been developed and are currently being investigated as potential treatments and/or cures for food allergy.

Keyword

food hypersensitivity; allergy; anaphylaxis; oral tolerance; immunotherapy

MeSH Terms

Adult
Allergens
Anaphylaxis
Child
Emergencies
Food Hypersensitivity
Humans
Hypersensitivity
Immunoglobulin E
Immunotherapy
Proteins
Allergens
Immunoglobulin E
Proteins

Reference

1. 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.

2. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. 2003. 112:1203–1207.

3. Grundy J, Matthews S, Bateman B, Dean T, Arshad SH. Rising prevalence of allergy to peanut in children: Data from 2 sequential cohorts. J Allergy Clin Immunol. 2002. 110:784–789.

4. Skripak JM, Matsui EC, Mudd K, Wood RA. The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007. 120:1172–1177.

5. Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol. 2007. 120:1413–1417.

6. Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The natural history of peanut allergy. J Allergy Clin Immunol. 2001. 107:367–374.

7. Fleischer DM, Conover-Walker MK, Matsui EC, Wood RA. The natural history of tree nut allergy. J Allergy Clin Immunol. 2005. 116:1087–1093.

8. Yu JW, Kagan R, Verreault N, Nicolas N, Joseph L, St Pierre Y, Clarke A. Accidental ingestions in children with peanut allergy. J Allergy Clin Immunol. 2006. 118:466–472.

9. Cohen BL, Noone S, Munoz-Furlong A, Sicherer SH. Development of a questionnaire to measure quality of life in families with a child with food allergy. J Allergy Clin Immunol. 2004. 114:1159–1163.

10. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992. 327:380–384.

11. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001. 107:191–193.

12. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol. 2007. 119:1016–1018.

13. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. 2001. 107:891–896.

14. Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. 2004. 114:144–149.

15. Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, Martin-Munoz F, Reche-Frutos M, Martin-Esteban M. Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant. J Allergy Clin Immunol. 2001. 107:185–190.

16. Boyano Martinez T, Garcia-Ara C, Diaz-Pena JM, Munoz FM, Garcia Sanchez G, Esteban MM. Validity of specific IgE antibodies in children with egg allergy. Clin Exp Allergy. 2001. 31:1464–1469.

17. Hill DJ, Heine RG, Hosking CS. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol. 2004. 15:435–441.

18. Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol. 2004. 114:387–391.

19. Nowak-Wegrzyn A, Muraro A. Food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol. 2009. 9:371–377.

20. Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast fed infants. J Pediatr. 1982. 101:906–910.

21. Sicherer SH, Sampson HA. Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. J Allergy Clin Immunol. 1999. 104:S114–S122.

22. Hill DJ, Hosking CS, de Benedictis FM, Oranje AP, Diepgen TL, Bauchau V. EPAAC Study Group. Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study. Clin Exp Allergy. 2008. 38:161–168.

23. Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, Flick J, Kelly J, Brown-Whitehorn T, Mamula P, Markowitz JE. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005. 3:1198–1206.

24. Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol. 2002. 109:363–368.

25. Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004. 351:940–941.

26. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, Liacouras CA. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr. 2009. 48:30–36.

27. Chase MW. Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc Soc Exp Biol Med. 1946. 61:257–259.

28. Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol. 2005. 115:3–12.

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

30. Lack G, Fox D, Northstone K, Golding J. Avon Longitudinal Study of Parents and Children Study Team. Factors associated with the development of peanut allergy in childhood. N Engl J Med. 2003. 348:977–985.

31. Bohle B. The impact of pollen-related food allergens on pollen allergy. Allergy. 2007. 62:3–10.

32. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007. 120:744–750.

33. Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+ CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J Exp Med. 2004. 199:1679–1688.

34. Li X, Huang CK, Schofield BH, Burks AW, Bannon GA, Kim KH, Huang SK, Sampson HA. Strain-dependent induction of allergic sensitization caused by peanut allergen DNA immunization in mice. J Immunol. 1999. 162:3045–3052.

35. Morafo V, Srivastava K, Huang CK, Kleiner G, Lee SY, Sampson HA, Li AM. Genetic susceptibility to food allergy is linked to differential TH2-TH1 responses in C3H/HeJ and BALB/c mice. J Allergy Clin Immunol. 2003. 111:1122–1128.

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

37. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, Fox AT, Turcanu V, Amir T, Zadik-Mnuhin G, Cohen A, Livne I, Lack G. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008. 122:984–991.

38. Untersmayr E, Scholl I, Swoboda I, Beil WJ, Forster-Waldl E, Walter F, Riemer A, Kraml G, Kinaciyan T, Spitzauer S, Boltz-Nitulescu G, Scheiner O, Jensen-Jarolim E. Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in Balb/c mice. J Allergy Clin Immunol. 2003. 112:616–623.

39. Untersmayr E, Bakos N, Scholl 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.

40. Takagi K, Teshima R, Okunuki H, Itoh S, Kawasaki N, Kawanishi T, Hayakawa T, Kohno Y, Urisu A, Sawada J. Kinetic analysis of pepsin digestion of chicken egg white ovomucoid and allergenic potential of pepsin fragments. Int Arch Allergy Immunol. 2005. 136:23–32.

41. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol. 1997. 159:1739–1745.

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

43. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy Clin Immunol. 2004. 4:285–290.

44. Miller MM, Miller MM. Beta-blockers and anaphylaxis: are the risks overstated? J Allergy Clin Immunol. 2005. 116:931–933. author reply 933-6.

45. Vadas P, Gold M, Perelman B, Liss GM, Lack G, Blyth T, Simons FE, Simons KJ, Cass D, Yeung J. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med. 2008. 358:28–35.

46. Jarvinen KM, Beyer K, Vila L, Chatchatee P, Busse PJ, Sampson HA. B-cell epitopes as a screening instrument for persistent cow's milk allergy. J Allergy Clin Immunol. 2002. 110:293–297.

47. Jarvinen KM, Beyer K, Vila L, Bardina L, Mishoe M, Sampson HA. Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy. Allergy. 2007. 62:758–765.

48. Shreffler WG, Lencer DA, Bardina L, Sampson HA. IgE and IgG4 epitope mapping by microarray immunoassay reveals the diversity of immune response to the peanut allergen, Ara h 2. J Allergy Clin Immunol. 2005. 116:893–899.

49. Wang J, Bardina L, Lencer DA, Shreffler WG, Sampson HA. Determination of epitope diversity in cow's milk hypersensitivity using microarray immunoassay. J Allergy Clin Immunol. 2006. 117:S39.

50. Flinterman AE, Knol EF, Lencer DA, Bardina L, den Hartog Jager CF, Lin J, Pasmans SG, Bruijnzeel-Koomen CA, Sampson HA, van Hoffen E, Shreffler WG. Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy. J Allergy Clin Immunol. 2008. 121:737–743.

51. Cerecedo I, Zamora J, Shreffler WG, Lin J, Bardina L, Dieguez MC, Wang J, Muriel A, de la Hoz B, Sampson HA. Mapping of the IgE and IgG4 sequential epitopes of milk allergens with a peptide microarray-based immunoassay. J Allergy Clin Immunol. 2008. 122:589–594.

52. Beyer K, Morrow E, Li XM, Bardina L, Bannon GA, Burks AW, Sampson HA. Effects of cooking methods on peanut allergenicity. J Allergy Clin Immunol. 2001. 107:1077–1081.

53. Shreffler WG, Castro RR, Kucuk ZY, Charlop-Powers Z, Grishina G, Yoo S, Burks AW, Sampson HA. The major glycoprotein allergen from Arachis hypogaea, Ara h 1, is a ligand of dendritic cell-specific ICAM-grabbing nonintegrin and acts as a Th2 adjuvant in vitro. J Immunol. 2006. 177:3677–3685.

54. Khodoun M, Strait R, Orekov T, Hogan S, Karasuyama H, Herbert DR, Kohl J, Finkelman FD. Peanuts can contribute to anaphylactic shock by activating complement. J Allergy Clin Immunol. 2009. 123:342–351.

55. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2007. 119:780–791.

56. Joint Task Force on Practice Parameters. Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology. American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 2003. 90(1):Suppl 1. 1–40.

57. Saltoun C, Avila PC. Advances in upper airway diseases and allergen immunotherapy in 2007. J Allergy Clin Immunol. 2008. 122:481–487.

58. Oppenheimer JJ, Nelson HS, Bock SA, Christensen F, Leung DYM. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol. 1992. 90:256–262.

59. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol. 1997. 99:744–751.

60. Alonso R, Enrique E, Pineda F, Basagana M, San Miguel-Moncin MM, Bartra J, Palacios R, Cistero-Bahima A. An observational study on outgrowing food allergy Turing non-birch pollen-specific, subcutaneous immunotherapy. Int Arch Allergy Immunol. 2007. 143:185–189.

61. Czarnecka-Operacz M, Jenerowicz D, Silny W. Oral allergy syndrome in patients with airborne pollen allergy treated with specific immunotherapy. Acta Dermatovenerol Croat. 2008. 16:19–24.

62. Wang J, Sicherer SH. Immunologic therapeutic approaches in the management of food allergy. Expert Rev Clin Immunol. 2009. 5:301–310.

63. Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, Matsui EC, Burks AW, Wood RA. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol. 2008. 122:1154–1160.

64. Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, Ventura A. Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008. 121:343–347.

65. Staden U, Blumchen K, Blankenstein N, Dannenberg N, Ulbricht H, Dobberstein K, Ziegert M, Niggemann B, Wahn U, Beyer K. Rush oral immunotherapy in children with persistent cow's milk allergy. J Allergy Clin Immunol. 2008. 122:418–419.

66. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zhong X, Burks AW. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009. 124:292–300.

67. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, Castello JV, Alonso R, de Mateo JA, Cerda-Trias T, San Miguel-Moncin Mdel M, Monzon S, Garcia M, Palacios R, Cistero-Bahima A. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005. 116:1073–1079.

68. Enrique E, Malek T, Pineda F, Palacios R, Bartra J, Tella R, Basagana M, Alonso R, Cistero-Bahima A. Sublingual immunotherapy for hazelnut food allergy: a follow-up study. Ann Allergy Asthma Immunol. 2008. 100:283–284.

69. Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, Diaz de Durana MD, Garcia BE, Gonzalez-Mancebo E, Martin S, Barber D, Rico P, Tabar AI. Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy. 2009. 64:876–883.

70. Kinaciyan T, Jahn-Schmid B, Radakovics A, Zwolfer 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 d 1. J Allergy Clin Immunol. 2007. 119:937–943.

71. King N, Helm R, Stanley JS, Vieths S, Luttkopf D, Hatahet L, Sampson H, Pons L, Burks W, Bannon GA. Allergenic characteristics of a modified peanut allergen. Mol Nutr Food Res. 2005. 49:963–971.

72. Bannon GA, Cockrell G, Connaughton C, West CM, Helm R, Stanley JS, King N, Rabjohn P, Sampson HA, Burks AW. Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int Arch Allergy Immunol. 2001. 124:70–72.

73. Ma Y, Gadermaier G, Bohle B, Bolhaar S, Knulst A, Markovic-Housley Z, Breiteneder H, Briza P, Hoffmann-Sommergruber K, Ferreira F. Mutational analysis of amino acid positions crucial for IgE-binding epitopes of the major apple (Maldus domestica) allergen, Mal d 1. Int Arch Allergy Immunol. 2006. 139:53–62.

74. Swoboda I, Bugajska-Schretter A, Linhart B, Verdino P, Keller W, Schulmeister U, Sperr WR, Valent P, Peltre G, Quirce S, Douladiris N, Papadopoulos NG, Valenta R, Spitzauer S. A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE-mediated fish allergy. J Immunol. 2007. 178:6290–6296.

75. Li XM, Srivastava K, Grishin A, Huang CK, Schofield B, Burks W, Sampson HA. Persistent protective effect of heat-killed Escherichia coli producing "engineered," recombinant peanut proteins in a murine model of peanut allergy. J Allergy Clin Immunol. 2003. 112:159–167.

76. Bissonnette EY, Befus AD. Inhibition of mast cell-mediated cytotoxicity by IFN-alpha/beta and -gamma. J Immunol. 1990. 145:3385–3390.

77. Pierkes M, Bellinghausen I, Hultsch T, Metz G, Knop J, Saloga J. Decreased release of histamine and sulfidoleukotrienes by human peripheral blood leukocytes after wasp venom immunotherapy is partially due to induction of IL-10 and IFN-gamma production of T cells. J Allergy Clin Immunol. 1999. 103:326–332.

78. Niederberger V, Reisinger J, Valent P, Krauth MT, Pauli G, van Hage M, Cromwell O, Horak F, Valenta R. Vaccination with genetically modified birch pollen allergens: immune and clinical effects on oral allergy syndrome. J Allergy Clin Immunol. 2007. 119:1013–1016.

79. Hong SJ, Michael JG, Fehringer A, Leung DY. Pepsin-digested peanut contains T-cell epitopes but no IgE epitopes. J Allergy Clin Immunol. 1999. 104:473–478.

80. Li S, Li XM, Burks AW, Bannon GA, Sampson HA. Modulation of peanut allergy by peptide-based immunotherapy. J Allergy Clin Immunol. 2001. 107:S233.

81. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV. CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med. 1997. 186:1623–1631.

82. Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, Eiden JJ, Kagey-Sobotka A, Creticos PS, Lichtenstein LM, Spiegelberg HL, Raz E. Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol. 2000. 106:124–134.

83. Horner AA, Nguyen MD, Ronaghy A, Cinman N, Verbeek S, Raz E. DNA-based vaccination reduces the risk of lethal anaphylactic hypersensitivity in mice. J Allergy Clin Immunol. 2000. 106:349–356.

84. Srivastava K, Li XM, Bannon GA, Burks AW, Eiden J, Vannest G, Tuck R, Rodriguez R, Sampson HA. Investigation of the use of Iss-linked Ara h2 for the treatment of peanut-induced allergy. J Allergy Clin Immunol. 2001. 107:S233.

85. Roy K, Mao HQ, Huang SK, Leong KW. Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med. 1999. 5:387–391.

86. Milgrom H. Anti-IgE therapy in allergic disease. Curr Opin Pediatr. 2004. 16:642–647.

87. Leung DY, Sampson HA, Yunginger JW, Burks AW Jr, Schneider LC, Wortel CH, Davis FM, Hyun JD, Shanahan WR Jr. Avon Longitudinal Study of Parents and Children Study Team. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med. 2003. 348:986–993.

88. Sampson HA. A phase II, randomized, double-blind, parallel group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy. J Allergy Clin Immunol. 2007. 119:S117.

89. Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, Mokhtarani M, Seyfert-Margolis V, Asare A, Bateman K, Deniz Y. Immune Tolerance Network Group. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006. 117:134–140.

90. Srivastava KD, Kattan JD, Zou ZM, Li JH, Zhang L, Wallenstein S, Goldfarb J, Sampson HA, Li XM. The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol. 2005. 115:171–178.

91. Srivastava KD, Zhang T, Qu C, Sampson HA, Li XM. Silencing peanut allergy: A Chinese Herbal Formula, Fahf-2, completely blocks peanut-induced anaphylaxis for up to 6 months following therapy in a murine model of peanut allergy. J Allergy Clin Immunol. 2006. 117:S328.

92. Srivastava KD, Sampson HA, Li XM. The traditional Chinese medicine formula FAHF-2 provides complete protection from anaphylaxis in a murine model of multiple food allergy. J Allergy Clin Immunol. 2009. 123:S151.

93. Ko J, Busse PJ, Shek L, Noone SA, Sampson HA, Li XM. Effect of Chinese herbal formulas on T-cell responses in patients with peanut allergy or asthma [abstract]. J Allergy Clin Immunol. 2005. 115:S34.

94. Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest. 2001. 107:83–90.

95. Straumann A, Bauer M, Fischer B, Blaser K, Simon HU. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol. 2001. 108:954–961.

96. Stein ML, Collins MH, Villanueva JM, Kushner JP, Putnam PE, Buckmeier BK, Filipovich AH, Assa'ad AH, Rothenberg ME. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol. 2006. 118:1312–1319.

97. Bryan SA, O'Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, Warrington SJ, Renzetti L, Rames A, Bock JA, Boyce MJ, Hansel TT, Holgate ST, Barnes PJ. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000. 356:2149–2153.

98. Cortes-Perez NG, Ah-Leung S, Bermudez-Humaran LG, Corthier G, Wal JM, Langella P, Adel-Patient K. Intranasal coadministration of live lactococci producing interleukin-12 and a major cow's milk allergen inhibits allergic reaction in mice. Clin Vaccine Immunol. 2007. 14:226–233.

99. Zhu FG, Kanimalla ER, Yu D, Sgarwal S. Oral administration of a synthetic agonist of Toll-like receptor 9 potently modulates peanut-induced allergy in mice. J Allergy Clin Immunol. 2007. 120:631–637.

100. Zhu D, Kepley CL, Zhang M, Zhang K, Saxon A. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med. 2002. 8:518–521.

101. Zhang K, Zhu D, Kepley C, Terada T, Saxon A. Chimeric human Fc gamma-allergen fusion proteins in the prevention of allergy. Immunol Allergy Clin North Am. 2007. 27:93–103.