title: Human Bone Marrow- and Adipose Tissue-derived Mesenchymal Stromal Cells are ImmunosuppressiveIn vitroand in a Humanized Allograft Rejection Model.
abstract: BACKGROUND
  Recent studies with bone marrow (BM)-derived Mesenchymal Stromal Cells (MSC) in transplant recipients demonstrate that treatment with MSC is safe and clinically feasible. While BM is currently the preferred source of MSC, adipose tissue is emerging as an alternative. To develop efficient therapies, there is a need for preclinical efficacy studies in transplantation. We used a unique humanized transplantation model to study thein vivoimmunosuppressive effect of human BM-MSC and adipose tissue-derived MSC (ASC).
  
  
  METHODS
  Gene expression of BM-MSC and ASC and their capacity to inhibit activated PBMC proliferation was evaluated. Thein vivoimmunosuppressive effect of BM-MSC and ASC was studied in a humanized mouse model. SCID mice were transplanted with human skin grafts and injected with human allogeneic PBMC with or without administration of BM-MSC or ASC. The effect of MSC on skin graft rejection was studied by immunohistochemistry and PCR.
  
  
  RESULTS
  BM-MSC and ASC expressed TGFβ, CXCL-10 and IDO. IDO expression and acitivity increased significantly in BM-MSC and ASC upon IFN-γ stimulation. IFN-γ stimulated BM-MSC and ASC inhibited the proliferation of activated PBMC in a significant and dose dependent manner. In our humanized mouse model, alloreactivity was marked by pronounced CD45+ T-cell infiltrates consisting of CD4+ and CD8+ T cells and increased IFN-γ expression in the skin grafts which were all significantly inhibited by both BM-MSC and ASC.
  
  
  CONCLUSIONS
  BM-MSC and ASC are immunosuppressivein vitroand suppress alloreactivity in a preclinical humanized transplantation model.
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Roemeling-van Rhijn
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Meriem
authors.initials: M
authors.lastname: Khairoun
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Korevaar
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lievers
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Leuning
authors.affiliation: General Surgery, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jan Nm
authors.initials: JN
authors.lastname: Ijzermans
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Michiel Gh
authors.initials: MG
authors.lastname: Betjes
authors.affiliation: Department of Biology, University of York, York, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Genever
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Hans Jw
authors.initials: HJ
authors.lastname: de Fijter
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.affiliation: Immunohematology and blood transfusion, Leiden University Medical Center, The Netherlands.
authors.forename: Helene
authors.initials: H
authors.lastname: Roelofs
authors.affiliation: Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hoogduijn
authors.affiliation: Nephrology, Leiden University Medical Center, The Netherlands.
authors.forename: Marlies E
authors.initials: ME
authors.lastname: Reinders
keywords: Adipose tissue; Allograft rejection; Bone marrow; Immunomodulation; Mesenchymal stromal cells