title: Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models.
abstract: BACKGROUND
  Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. These mechanisms were demonstrated by administering bone marrow derived human MSCs (hMSCs) to graft versus host disease (GVHD) murine models.
  
  
  METHODS
  BALB/c host mice were irradiated prior to receiving C57BL/6 donor T cell depleted bone marrow (TCDBM) cells (negative control) and donor CD4+ T lymphocyte with (treatment group) or without hMSCs (positive control). The presence of hMSCs in target tissues and lymphoid organs was documented by using in vivo imaging and measuring the expression of EphB2 and ephrin-B2 by RTqPCR. Survival rate and GVHD score were also monitored. Tissue sections were obtained for histopathologic analysis. Flow cytometry was used to document donor T cell alloreactivity and expression of CCR5, CXCR3 and CCR7. ELISA was utilized to determine levels of proinflammatory cytokines, RANTES (CCL5) and phosphorylated STAT 5A/B. RTqPCR was performed to quantify expression of CCL3 and CXCL9. Western blotting was performed to qualitatively measure iNOS expression.
  
  
  RESULTS
  Survival rate and GVHD score improved with hMSC treatment. Pathologic changes of GVHD were abrogated. Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs. Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.
  
  
  CONCLUSIONS
  These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.
authors.forename: Joseph Delano
authors.initials: JD
authors.lastname: Robles
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.
authors.forename: Yin Ping
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong.
authors.forename: Michael
authors.initials: M
authors.lastname: Manio
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong.
authors.forename: Eva Hc
authors.initials: EH
authors.lastname: Tang
authors.affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.
authors.forename: Godfrey Chi-Fung
authors.initials: GC
authors.lastname: Chan
keywords: Bone marrow transplantation; GVHD; Immunosuppression; MSC