title: Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease.
abstract: BACKGROUND
  Multipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo.
  
  
  METHODS
  We examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major histocompatibility complex-mismatched: UBI-GFP/BL6 [H-2(b)]→BALB/c [H-2(d)] and the sibling transplant mimic, UBI-GFP/BL6 [H-2(b)]→BALB.B [H-2(b)]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients.
  
  
  RESULTS
  Despite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graft-versus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-γ, an important mediator of graft-versus-host disease.
  
  
  CONCLUSIONS
  Mesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-γ. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.
authors.affiliation: Bone Marrow Transplant Team, Mater Medical Research Institute, South Brisbane QLD 4101 Australia.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Christensen
authors.forename: Brie E
authors.initials: BE
authors.lastname: Turner
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sinfield
authors.forename: Katarina
authors.initials: K
authors.lastname: Kollar
authors.forename: Hannah
authors.initials: H
authors.lastname: Cullup
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waterhouse
authors.forename: Derek N J
authors.initials: DN
authors.lastname: Hart
authors.forename: Kerry
authors.initials: K
authors.lastname: Atkinson
authors.forename: Alison M
authors.initials: AM
authors.lastname: Rice
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma
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