title: Peyer's patches and mesenteric lymph nodes cooperatively promote enteropathy in a mouse model of food allergy.
abstract: OBJECTIVE
  To improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23-3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation.
  
  
  RESULTS
  OVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T-cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T-cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy.
  
  
  CONCLUSIONS
  PPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy.
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.
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.
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: Kyoko
authors.initials: K
authors.lastname: Shibahara
authors.affiliation: Biotechnical Center (BT Center), Japan SLC, Inc., Shizuoka, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Makino
authors.affiliation: Department of Food and Nutrition, Faculty of Human Sciences and Design, Japan Women's University, Tokyo, Japan.
authors.forename: Masae
authors.initials: M
authors.lastname: Goseki-Sone
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Miran
authors.initials: M
authors.lastname: Kihara-Fujioka
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 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.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kurashima
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Igarashi
authors.affiliation: Department of Microbiology and Immunology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamamoto
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; Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.affiliation: Vice President's Research Group "Molecular Allergology", Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Masako
authors.initials: M
authors.lastname: Toda
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: D000821:Animal Feed; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004529:Egg White; D005260:Female; D005512:Food Hypersensitivity / Q000276:immunology* / Q000473:pathology; D015847:Interleukin-4 / Q000096:biosynthesis; D007410:Intestinal Diseases / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology*; D008297:Male; D008643:Mesentery; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010581:Peyer's Patches / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D015847:Interleukin-4; D010047:Ovalbumin