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Vol. 161, Suppl. 2, 2013
Issue release date: May 2013
Int Arch Allergy Immunol 2013;161(suppl 2):164-169

Oral Immunotherapy for Allergic Diseases Using Transgenic Rice Seeds: Current State and Future Prospects

Saeki M. · Nishimura T. · Mori A. · Hiroi T.
aAllergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, and bClinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital, Sagamihara, Japan

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Allergen-specific immunotherapy (IT) has been shown to provide clinical benefit for patients with allergic diseases. At present, subcutaneous and sublingual ITs are mainly authorized for clinical treatment. Oral administration of allergens seems to be the easiest way to achieve IT, though it has yet to be translated to the clinical setting, mainly due to the requirement of a large amount of allergens. Plants, especially rice seeds, have recently been recognized as superior allergen carriers for oral administration, because of their high productivity, stability and safety. Therefore, in order to establish clinically applicable oral IT, we have been developing transgenic rice seeds (Tg rice), in which major epitopes of cedar pollen allergens or house-dust mites (HDM) are expressed. The efficacy of this orally administered Tg rice was confirmed in murine models of allergic rhinitis and bronchial asthma. In the safety study of the Tg rice, no adverse effects on cynomolgus macaques were observed. In this review, we summarized the current state and future prospects of allergen-specific IT, focusing particularly on oral IT with allergen-expressing Tg rice.

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  1. Dahl R, Andersen PS, Chivato T, Valovirta E, de Monchy J: National prevalence of respiratory allergic disorders. Respir Med 2004;98:398-403.
  2. Noon L: Prophylactic inoculation against hay fever. Lancet 1911;177:1572-1573.

    External Resources

  3. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, Staple SQ, Aalberse RC, Till SJ, Durham SR: Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 2004;172:3252-3259.

    External Resources

  4. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA: IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003;33:1205-1214.
  5. Pilette C, Nouri-Aria KT, Jacobson MR, Wilcock LK, Detry B, Walker SM, Francis JN, Durham SR: Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J Immunol 2007;178:4658-4666.

    External Resources

  6. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994;265:1237-1240.
  7. Friedman A, Weiner HL: Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci USA 1994;91:6688-6692.
  8. Whitacre CC, Gienapp IE, Orosz CG, Bitar DM: Oral tolerance in experimental auto- immune encephalomyelitis. III. Evidence for clonal anergy. J Immunol 1991;147:2155-2163.

    External Resources

  9. Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo VK, Weiner HL: Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995;376:177-180.
  10. Akdis CA: Therapies for allergic inflammation: refining strategies to induce tolerance. Nat Med 2012 4;18:736-749.
  11. Jutel M, Solarewicz-Madejek K, Smolińska S: The future of antigen-specific immunotherapy of allergy. Drug Information J, DOI: 10.1177/0092861512456283.

    External Resources

  12. McBride D, Keil T, Grabenhenrich L, Dubakiene R, Drasutiene G, Fiocchi A, Dahdah L, Sprikkelman AB, Schoemaker AA, Roberts G, Grimshaw K, Kowalski ML, Stanczyk-Przyluska A, Sigurdardottir S, Clausen M, Papadopoulos NG, Mitsias D, Rosenfeld L, Reche M, Pascual C, Reich A, Hourihane J, Wahn U, Mills EN, Mackie A, Beyer K: The EuroPrevall birth cohort study on food allergy: baseline characteristics of 12,000 newborns and their families from nine European countries. Pediatr Allergy Immunol 2012;23:230-239.
  13. Bousquet J, Lockey R, Malling HJ, Alvarez-Cuesta E, Canonica GW, Chapman MD, Creticos PJ, Dayer JM, Durham SR, Demoly P, Goldstein RJ, Ishikawa T, Ito K, Kraft D, Lambert PH, Løwenstein H, Müller U, Norman PS, Reisman RE, Valenta R, Valovirta E, Yssel H: Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American Academy of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998;81:401-405.

    External Resources

  14. Cox L, Li JT, Nelson H, Lockey R: Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol 2007;120: S25-S85.
  15. Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, Potter PC, Bousquet PJ, Cox LS, Durham SR, Nelson HS, Passalacqua G, Ryan DP, Brozek JL, Compalati E, Dahl R, Delgado L, van Wijk RG, Gower RG, Ledford DK, Filho NR, Valovirta EJ, Yusuf OM, Zuberbier T, Akhanda W, Almarales RC, Ansotegui I, Bonifazi F, Ceuppens J, Chivato T, Dimova D, Dumitrascu D, Fontana L, Katelaris CH, Kaulsay R, Kuna P, Larenas-Linnemann D, Manoussakis M, Nekam K, Nunes C, O'Hehir R, Olaguibel JM, Onder NB, Park JW, Priftanji A, Puy R, Sarmiento L, Scadding G, Schmid-Grendelmeier P, Seberova E, Sepiashvili R, Solé D, Togias A, Tomino C, Toskala E, Van Beever H, Vieths S: Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy 2009;64:1-59.
  16. Marcucci F, Sensi LG, Caffarelli C, Cavagni G, Bernardini R, Tiri A, Riva G, Novembre E: Low-dose local nasal immunotherapy in children with perennial allergic rhinitis due to Dermatophagoides. Allergy 2002;57:23-28.
  17. Patriarca G, Nucera E, Roncallo C, Pollastrini E, Bartolozzi F, De Pasquale T, Buonomo A, Gasbarrini G, Di Campli C, Schiavino D: Oral desensitizing treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 2003;17:459-465.
  18. Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG: A protocol for oral desensitization in children with IgE-mediated cow's milk allergy. Allergy 2004;59:980-987.
  19. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K: Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007;62:1261-1269.
  20. Shin JH, Kang JM, Kim SW, Cho JH, Park YJ, Kim SW: Effect of oral tolerance in a mouse model of allergic rhinitis. Otolaryngol Head Neck Surg 2010;142:370-375.
  21. Vaickus LJ, Bouchard J, Kim J, Natarajan S, Remick DG: Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study. Respir Res 2010;11:160.
  22. Taudorf E, Laursen LC, Lanner A, Björksten B, Dreborg S, Søborg M, Weeke B: Oral immunotherapy in birch pollen hay fever. J Allergy Clin Immunol 1987;80:153-161.
  23. Takaiwa F: A rice-based edible vaccine expressing multiple T-cell epitopes to induce oral tolerance and inhibit allergy. Immunol Allergy Clin North Am 2007;27:129-139.
  24. Fischer R, Emans N: Molecular farming of pharmaceutical proteins. Transgenic Res 2000;9:279-299.
  25. Giddings G: Transgenic plants as protein factories. Curr Opin Biotechnol 2001;12:450-454.
  26. Daniell H, Streatfield SJ, Wycoff K: Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants. Trends Plant Sci 2001;6:219-226.
  27. Shewry PR, Halford NG: Cereal seed storage proteins: structures, properties and role in grain utilization. J Exp Bot 2002;53:947-958.
  28. Okuda M: Epidemiology of Japanese cedar pollinosis throughout Japan. Ann Allergy Asthma Immunol 2003;91:288-296.
  29. Yasueda H, Yui Y, Shimizu T, Shida T: Isolation and partial characterization of the major allergen from Japanese cedar (Cryptomeria japonica) pollen. J Allergy Clin Immunol 1983;71:77-86.
  30. Sakaguchi M, Inouye S, Taniai M, Ando S, Usui M, Matuhasi T: Identification of the second major allergen of Japanese cedar pollen. Allergy 1990;45:309-312.
  31. Takagi H, Hiroi T, Yang L, Tada Y, Yuki Y, Takamura K, Ishimitsu R, Kawauchi H, Kiyono H, Takaiwa F: A rice-based edible vaccine expressing multiple T cell epitopes induces oral tolerance for inhibition of Th2-mediated IgE responses. Proc Natl Acad Sci USA 2005;102:17525-17530.
  32. Thomas WR, Smith WA, Hales BJ, Mills KL, O'Brien RM: Characterization and immunobiology of house dust mite allergens. Int Arch Allergy Immunol 2002;129:1-18.
  33. Platt-Mills TA, Sporik RB, Chapman MD, Heymann PW: The role of indoor allergens in asthma. Allergy 1995;50:S5-S12.
  34. Platts-Mills TA, Vervloet D, Thomas WR, Aalberse RC, Chapman MD: Indoor allergens and asthma: report of the Third International Workshop. J Allergy Clin Immunol 1997;100:S2-S24.
  35. Suzuki K, Kaminuma O, Yang L, Motoi Y, Takai T, Ichikawa S, Okumura K, Ogawa H, Mori A, Takaiwa F, Hiroi T: Development of transgenic rice expressing mite antigen for a new concept of immunotherapy. Int Arch Allergy Immunol 2009;149:S21-S24.
  36. Suzuki K, Kaminuma O, Yang L, Takai T, Mori A, Umezu-Goto M, Ohtomo T, Ohmachi Y, Noda Y, Hirose S, Okumura K, Ogawa H, Takada K, Hirasawa M, Hiroi T, Takaiwa F: Prevention of allergic asthma by vaccination with transgenic rice seed expressing mite allergen: induction of allergen-specific oral tolerance without bystander suppression. Plant Biotechnol J 2011;9:982-990.
  37. Saeki M, Nishimura T, Kaminuma O, Suzuki K, Takai T, Mori A, Takaiwa F, Hiroi T: Inhibition of allergen-induced airway inflammation by oral immunotherapy with transgenic rice seeds independently of immunoglobulin E synthesis. Int Arch Allergy Immunol 2012;158:S66-S69.
  38. Hirahara K, Saito S, Serizawa N, Sasaki R, Sakaguchi M, Inouye S, Taniguchi Y, Kaminogawa S, Shiraishi A: Oral administration of a dominant T-cell determinant peptide inhibits allergen-specific Th1 and Th2 cell responses in Cry j 2-primed mice. J Allergy Clin Immunol 1998;102:961-967.
  39. Hirahara K, Tatsuta T, Takatori T, Ohtsuki M, Kirinaka H, Kawaguchi J, Serizawa N, Taniguchi Y, Saito S, Sakaguchi M, Inouye S, Shiraishi A: Preclinical evaluation of an immunotherapeutic peptide comprising 7 T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen allergens. J Allergy Clin Immunol 2001;108:94-100.
  40. Takagi H, Hirose S, Yasuda H, Takaiwa F: Biochemical safety evaluation of transgenic rice seeds expressing T cell epitopes of Japanese cedar pollen allergens. J Agric Food Chem 2006;54:9901-9905.
  41. Takagi H, Saito S, Yang L, Nagasaka S, Nishizawa N, Takaiwa F: Oral immunotherapy against a pollen allergy using a seed-based peptide vaccine. Plant Biotech J 2005;3:521-533.
  42. Domon E, Takagi H, Hirose S, Sugita K, Kasahara S, Ebinuma H, Takaiwa F: 26-Week oral safety study in macaques for transgenic rice containing major human T-cell epitope peptides from Japanese cedar pollen allergens. J Agric Food Chem 2009;57:5633-5648.

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