title: Critical role of intestinal interleukin-4 modulating regulatory T cells for desensitization, tolerance, and inflammation of food allergy.
abstract: OBJECTIVE
  The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors.
  
  
  METHODS
  OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2-28 days. Interleukin (IL)-4 production by CD4+ T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3+ OVA-specific Tregs (aiTreg) in this process.
  
  
  RESULTS
  Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7-10, in EW-fed D10 and RD10 mice, splenic CD4+ T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4+ T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice.
  
  
  CONCLUSIONS
  Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Haruyo
authors.initials: H
authors.lastname: Nakajima-Adachi
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shibahara
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fujimura
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takeyama
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Hiraide
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Department of Food Bioscience and Biotechnology, Nihon University, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Department of Food Bioscience and Biotechnology, Nihon University, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hosono
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nochi
authors.affiliation: Department of Clinical Bio-regulatory Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Wakatsuki
authors.affiliation: The Department of Pediatrics, Chiba University, Chiba, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Department of Food Bioscience and Biotechnology, Nihon University, Kanagawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaminogawa
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.|International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan.|Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.|Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hachimura
mesh_terms: D000485:Allergens / Q000009:adverse effects / Q000276:immunology*; D000818:Animals; D003888:Desensitization, Immunologic; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D010047:Ovalbumin / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D010047:Ovalbumin