title: Prolongation of composite tissue allotransplant survival by treatment with bone marrow mesenchymal stem cells is correlated with T-cell regulation in a swine hind-limb model.
abstract: BACKGROUND
  Recently published reports indicate that treatment with mesenchymal stem cells combined with bone marrow transplantation could prolong survival after composite tissue allotransplantation. This study investigated whether bone marrow mesenchymal stem cells combined with irradiation and short-term immunosuppressant therapy, but without bone marrow transplantation, could prolong composite tissue allotransplantation survival. Correlation with regulatory T-cell populations was also evaluated in a swine hind-limb model.
  
  
  METHODS
  Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n = 4) was the untreated control. Group II (n = 3) received mesenchymal stem cells alone (on days -1, 3, 7, 14, and 21). Group III (n = 5) received cyclosporine A (on days 0 through 28). Group IV (n = 3) received irradiation (on day -1), mesenchymal stem cells (on days 1, 7, 14, and 21), and cyclosporine A (on days 0 to 28). Swine viability and signs of allograft rejection were monitored postoperatively. Histopathologic changes in allografts were examined. The expression and localization of CD4+/CD25+ and CD4+/FoxP3+ T cells were assessed using flow cytometry and immunohistochemistry.
  
  
  RESULTS
  Treatment with mesenchymal stem cells along with irradiation and cyclosporine A resulted in significant increases in allograft survival as compared with other groups (>120 days; p = 0.018). Histologic examination revealed the lowest degree of rejection in grafted skin and interstitial muscle layers in the mesenchymal stem cell/irradiation/cyclosporine A group. Flow cytometric analysis revealed a significant increase in the percentage of CD4+/CD25+ and CD4+/FoxP3+ T cells in both the blood and graft in the mesenchymal stem cell/irradiation/cyclosporine A group.
  
  
  CONCLUSIONS
  These results suggest that prolonged survival after composite tissue allotransplantation induced by treatment with mesenchymal stem cells combined with irradiation/cyclosporine A is correlated with regulatory T cells.
authors.affiliation: Kaohsiung, Taiwan From the Department of Plastic and Reconstructive Surgery, Department of Medical Research, Liver Transplantation Program, and Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine.
authors.forename: Yur-Ren
authors.initials: YR
authors.lastname: Kuo
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Chen
authors.forename: Hsiang-Shun
authors.initials: HS
authors.lastname: Shih
authors.forename: Shigeru
authors.initials: S
authors.lastname: Goto
authors.forename: Chong-Wei
authors.initials: CW
authors.lastname: Huang
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Wang
authors.forename: Chao-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Fu-Chan
authors.initials: FC
authors.lastname: Wei
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016572:Cyclosporine / Q000627:therapeutic use; D006085:Graft Survival; D006614:Hindlimb / Q000637:transplantation; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D045164:Mesenchymal Stem Cell Transplantation; D023421:Models, Animal; D013552:Swine; D013556:Swine, Miniature; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine