title: Regulatory T-cell suppression of CD8+ T-cell-mediated graft-versus-host reaction requires their presence during priming.
abstract: BACKGROUND
  Despite the promising therapeutic potential of regulatory T cells (Treg) in animal studies of graft-versus-host disease (GVHD), little is known about their effect on human GVHD. Whether Treg are capable of ameliorating GVHD tissue damage has never been demonstrated in humans. It is also unknown whether Treg modulation of GVH histopathologic damage relies on their presence during effector T-cell priming, or whether allogeneic Treg are safe to use clinically.
  
  
  METHODS
  To address these questions, we used an in vitro human skin explant GVHD model, which mimics the physiopathology of GVHD. First, "donor"-derived CD8 T cells were stimulated with human leukocyte antigen-unmatched "recipient" dendritic cells (priming phase), then primed "donor" CD8 T cells were co-cultured with "recipient" skin to induce GVH tissue damage (effector phase). "Donor"-derived Treg were added at the priming or effector phase of the GVH response. Histopathologic changes in the skin were evaluated using a clinically validated GVHD scoring system.
  
  
  RESULTS
  "Donor"-derived Treg significantly reduced the severity of GVH histopathologic damage when present during T-cell priming. In contrast, Treg failed to prevent GVH tissue damage when added to the skin co-culture (effector phase), concurrently with primed T cells. Importantly, "donor" Treg alone did not induce GVH tissue damage. Delayed Treg addition led to reduced and impaired Treg suppression of CD8 T-cell activation and their cytolytic function.
  
  
  CONCLUSIONS
  "Donor"-derived Treg effectively suppress CD8 T-cell-mediated GVH tissue damage but are critically required during priming of effector T cells. "Donor"-derived Treg seem to be safe and do not induce GVH histopathologic damage.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom. X.N.Wang@ncl.ac.uk
authors.forename: Xiao-Nong
authors.initials: XN
authors.lastname: Wang
authors.forename: Muzlifah A
authors.initials: MA
authors.lastname: Haniffa
authors.forename: Udo
authors.initials: U
authors.lastname: Holtick
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Collin
authors.forename: Graham
authors.initials: G
authors.lastname: Jackson
authors.forename: Catharien M U
authors.initials: CM
authors.lastname: Hilkens
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.forename: Matthias
authors.initials: M
authors.lastname: Edinger
authors.forename: Petra
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dickinson
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control; D006087:Graft vs Host Reaction / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006789:Host vs Graft Reaction / Q000276:immunology; D006801:Humans; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014182:Transplantation, Autologous
chemical_list: D015703:Antigens, CD