title: Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats.
abstract: BACKGROUND
  The transcription factor forkhead box P3 (Foxp3) is a master regulatory gene necessary for the development and function of CD4(+)CD25(+) regulatory T cells (Tregs). Mesenchymal stem cells (MSC) have recently emerged as promising candidates for cell-based immunosuppression/tolerance induction protocols. Thus, we hypothesized that MSC-based Foxp3 gene therapy would improve immunosuppressive capacity of MSC and induce donor-specific allograft tolerance in rat's liver allograft model.
  
  
  METHODS
  The present study utilized a lentivirus vector to overexpress the therapeutic gene Foxp3 on MSC. In vivo, Injections of 2 × 10(6) MSC, FUGW-MSC or Foxp3-MSC into the portal vein were carried out immediately after liver transplantation.
  
  
  RESULTS
  Successful gene transfer of Foxp3 in MSC was achieved by lentivirus carrying Foxp3 and Foxp3-MSC engraftment in liver allograft was confirmed by fluorescence microscopy. Foxp3-MSC treatment significantly inhibited the proliferation of allogeneic ACI CD4(+) T cells to splenocytes (SC) from the same donor strain or third-party BN rat compared with MSC. Foxp3-MSC suppressive effect on the proliferation of CD4(+) T cells is contact dependent and associated with Programmed death ligand 1(PD-L1) upregulation in MSC. Co-culture of CD4(+) T cells with Foxp3-MSC results in a shift towards a Tregs phenotype. More importantly, Foxp3-MSC monotherapy achieved donor-specific liver allograft tolerance and generated a state of CD4(+)CD25(+)Foxp3(+) Tregs-dependent tolerance.
  
  
  CONCLUSIONS
  Foxp3-engineered MSC therapy seems to be a promising and attractive cell therapy approach for inducing immunosuppression or transplant tolerance.
authors: Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China. Qi_hz@126.com.
authors: Haizhi
authors: H
authors: Qi
authors: Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China. chen_guangshun@sina.com.
authors: Guangshun
authors: G
authors: Chen
authors: Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China. 546701954@QQ.com.
authors: Yaxun
authors: Y
authors: Huang
authors: Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China. szz5858@medmail.com.cn.
authors: Zhongzhou
authors: Z
authors: Si
authors: Department of Organ Transplantation, Second Xiangya Hospital, Central South University, 139 RenMin Road, Changsha, Hunan, China. lijiequn2002@hotmail.com.
authors: Jiequn
authors: J
authors: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002450:Cell Communication; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006085:Graft Survival / Q000276:immunology; D056747:Immunomodulation; D007165:Immunosuppression Therapy; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D014161:Transduction, Genetic; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors