title: Indoleamine 2, 3-Dioxgenase Transfected Mesenchymal Stem Cells Induce Kidney Allograft Tolerance by Increasing the Production and Function of Regulatory T Cells.
abstract: BACKGROUND
  The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well characterized in vitro. However, the role of MSCs in organ transplantation remains unclear. The purpose of this study was to examine the role of indoleamine 2, 3-dioxgenase (IDO)-transfected MSCs in immunoregulation both in vitro and in vivo.
  
  
  METHODS
  Wild-type (WT) MSCs, empty lentivirus-transfected MSCs (Lenti-MSCs) or IDO-lentivirus-transfected MSCs (IDO-MSCs) were cocultured with peripheral blood mononuclear cells (PBMCs) or CD4CD25 regulatory T (Treg) cells to examine the impact of IDO on the immunoregulatory properties of MSCs in vitro. WT-MSCs, Lenti-MSCs or IDO-MSCs (2 × 10/kg) were intravenously injected into rabbit renal transplant recipients immediately after surgery to examine the role of IDO-MSCs in tolerance induction in vivo.
  
  
  RESULTS
  Lentivirus infection of MSCs resulted in stable expression of IDO. The IDO-MSCs inhibited the proliferation of CD4CD25 effector T cells to a greater extent than WT-MSCs. Coculture of PBMCs and IDO-MSCs induced a higher percentage of CD4CD25Foxp3 Treg cells in PBMCs. Additionally, the antigen-specific suppressive function of these CD4CD25 Treg cells was increased. The IDO-MSCs-treated Treg cells showed upregulated expression of cytotoxic T-lymphocyte-associated antigen 4 and increased secretion of IL-10 and TGF-β. Low doses of IDO-MSCs prolonged graft survival and induced tolerance by inducing antigen-specific CD4CD25 Treg cells, as evidenced by the finding that IDO-MSCs-treated kidney transplant recipients accepted donor-specific skin grafts but rejected third-party grafts.
  
  
  CONCLUSIONS
  The IDO increased the direct immunoregulatory properties of MSCs. The IDO-MSCs enhanced the expression and function of CD4CD25 Foxp3 Treg cells and induced allograft tolerance.
authors: 1 Department of Nephrology, Southwest Hospital, the Third Military Medical University, Chongqing, 400038, P.R. China.
authors: Yue
authors: Y
authors: He
authors: Shan
authors: S
authors: Zhou
authors: Hong
authors: H
authors: Liu
authors: Bingbing
authors: B
authors: Shen
authors: Hongwen
authors: H
authors: Zhao
authors: Kanfu
authors: K
authors: Peng
authors: Xiongfei
authors: X
authors: Wu
mesh_terms: D064591:Allografts; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000276:immunology; D011817:Rabbits; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection / Q000379:methods; D023001:Transplantation Tolerance
chemical_list: D015415:Biomarkers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase