title: Amelioration of acute graft-versus-host disease by adoptive transfer of ex vivo expanded human cord blood CD4+CD25+ forkhead box protein 3+ regulatory T cells is associated with the polarization of Treg/Th17 balance in a mouse model.
abstract: BACKGROUND
  Human cord blood (CB) is a superior source of regulatory T cells (Tregs) compared with peripheral blood. Initial studies have shown that CB-derived Tregs can be effectively expanded ex vivo. However, in vitro suppressor activity of expanded CB-Tregs and their efficacy in the prevention of acute graft-versus-host disease (aGVHD) in vivo are poorly understood.
  
  
  METHODS
  In vitro, human CB CD4+CD25+ T cells expanded with anti-CD3/CD28 beads plus interleukin (IL)-2 and the phenotypes, expression of cytokines, and suppression of expanded cells were analyzed after two cycles of stimulation. In vivo, the addition of human CB-Tregs was transferred in the major histocompatibility complex-mismatched aGVHD mouse model. Survival, body weight, GVHD scoring, histopathologic specimens, serum cytokines, and Th subsets were analyzed in CB-Treg-treated mice and untreated controls.
  
  
  RESULTS
  After being expanded ex vivo, human CB-derived Tregs with potent suppressor function could meet clinical demands. Up to 85% of mice with CB-Tregs treatment survived beyond Day 63 after bone marrow transplantation; however, all aGVHD mice died within 18 days. In the serum of the CB-Treg-treated mice, the production of transforming growth factor-β increased continuously, as opposed to IL-17, which decreased quickly. Consistent with the changes of cytokines, the percentage of mouse CD4+ forkhead box protein 3+ Tregs increased while that of Th17 cells decreased.
  
  
  CONCLUSIONS
  Ex vivo expanded human CB-Tregs significantly prevented allogeneic aGVHD in vivo by modulating various cytokine secretion and polarizing the Treg/Th17 balance toward Treg, which suggests the potential use of expanded CB-Tregs as a therapeutic approach for GVHD.
authors.affiliation: Blood Engineering Laboratory, Shanghai Blood Center, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Huahua
authors.initials: H
authors.lastname: Fan
authors.forename: Jun
authors.initials: J
authors.lastname: Hao
authors.forename: Yana
authors.initials: Y
authors.lastname: Ren
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Guiping
authors.initials: G
authors.lastname: Li
authors.forename: Rufeng
authors.initials: R
authors.lastname: Xie
authors.forename: Yiming
authors.initials: Y
authors.lastname: Yang
authors.forename: Kaicheng
authors.initials: K
authors.lastname: Qian
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016764:Cell Polarity / Q000276:immunology / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit