title: Enhanced production of CCL18 by tolerogenic dendritic cells is associated with inhibition of allergic airway reactivity.
abstract: BACKGROUND
  IL-10-treated dendritic cells (DCs) have been shown to inhibit T-cell responses through induction of anergy and regulatory T cells in various model systems, including allergic inflammation, but the factors being involved in this inhibition are still unclear.
  
  
  OBJECTIVE
  This study set out to analyze such factors produced or induced by IL-10-treated DCs by using gene expression profiling and to explore their function.
  
  
  METHODS
  CD4(+) T cells from allergic donors were stimulated with autologous monocyte-derived allergen-pulsed mature DCs or IL-10-treated DCs. After 24 hours, the transcriptional profile was analyzed by using Affymetrix technology. Results were validated by using quantitative real-time PCR, protein expression, and functional in vitro and in vivo studies.
  
  
  RESULTS
  In CD4(+) T-cell/IL-10-treated DC cocultures the expression of several known genes, such as IL13, IL5 and OX40, was suppressed. Interestingly, there was only one factor that was strongly upregulated: the DC-derived chemokine CCL18. In vitro addition of CCL18 to cocultures of CD4(+) T cells and allergen-pulsed DCs resulted in a similar inhibition of T(H)2 cytokine production as induced by allergen-pulsed IL-10-treated DCs without exogenous CCL18, whereas T(H)1 cytokine production, IL-10 production, and proliferation were not affected. Furthermore, in a humanized mouse model of allergy using PBMC-engrafted NOD-scid-γc(-/-) mice, CCL18, but not another T(H)2-associated chemokine, CCL17, inhibited airway reactivity and lung inflammation. Chemotaxis assays revealed that CCL18 preferentially attracted regulatory T cells and, less efficiently, T(H)2 cells.
  
  
  CONCLUSIONS
  These data demonstrate that CCL18 might represent a molecule of significant importance in immunoregulation and might be a therapeutic target in patients with allergic airway diseases.
authors.affiliation: Department of Dermatology, University Medical Center, Johannes-Gutenberg-Universität Mainz, Mainz, Germany. iris.bellinghausen@unimedizin-mainz.de
authors.forename: Iris
authors.initials: I
authors.lastname: Bellinghausen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.forename: Helen
authors.initials: H
authors.lastname: Martin
authors.forename: Joachim
authors.initials: J
authors.lastname: Maxeiner
authors.forename: Uli
authors.initials: U
authors.lastname: Luxemburger
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Joachim
authors.initials: J
authors.lastname: Saloga
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D046228:Microarray Analysis; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059467:Transcriptome
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D016753:Interleukin-10