title: SAMP1/YitFc mice develop ileitis via loss of CCL21 and defects in dendritic cell migration.
abstract: OBJECTIVE
  The lymphatic chemokine CCL21 is required for dendritic cell (DC) migration from tissues to lymph nodes, which helps establish tolerance to foreign yet harmless antigens. We demonstrate that CCL21 is almost completely absent from SAMP1/YitFc (SAMP) mice, which spontaneously develop chronic ileitis that resembles Crohn's disease, and that DC migration is severely impaired in these mice compared with AKR mice (controls). Toll-like receptor agonists like the Toll-like receptor 7 agonist R848 induce DC maturation and mobilization.
  
  
  METHODS
  We collected intestinal and other tissues and mesenteric lymph nodes (MLN) from SAMP mice. Expression of CCL21 was measured by quantitative reverse transcription polymerase chain reaction and immunofluorescence analyses; spontaneous and induced migration of DCs were assessed by flow cytometry. We analyzed production of retinoic acid by DCs and their ability to induce development of regulatory T cells. Mice were fed R848 to determine its effects on migration of DCs and development of ileitis in SAMP mice.
  
  
  RESULTS
  SAMP mice expressed almost no CCL21 in any tissue tested. Their CD11b(+)CD103(+) DCs were defective in migration from the ileal lamina propria to the MLN. DCs from SAMP mice also had a greatly reduced ability to produce retinoic acid and induce development of regulatory T cells compared with control mice. Young SAMP mice had reduced CCL21 expression and decreased DC migration before developing ileitis. Administration of R848 to adult SAMP mice increased migration of DC to the MLN and development of regulatory T cells there, and reduced the severity of ileitis.
  
  
  CONCLUSIONS
  Loss of CCL21 signaling and DC migration is required for development of ileitis in SAMP mice. Reagents such as R848, which activate DC migration to the MLN, may be developed as treatments for patients with Crohn's disease.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Mikulski
authors.affiliation: Department of Pathology, University of California-San Diego, San Diego, California.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Johnson
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.affiliation: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Gisen
authors.initials: G
authors.lastname: Kim
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Heba
authors.initials: H
authors.lastname: Nowyhed
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Wendy
authors.initials: W
authors.lastname: Goodman
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Chodaczek
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California. Electronic address: klaus@liai.org.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D054421:Chemokine CCL21 / Q000235:genetics / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D007079:Ileitis / Q000276:immunology*; D007093:Imidazoles / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D054421:Chemokine CCL21; D007093:Imidazoles; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C402365:resiquimod
keywords: CD; Immune Regulation; Oral Tolerance; Small Intestine