title: Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model.
abstract: BACKGROUND
  Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved.
  
  
  METHODS
  We engrafted human pancreatic islets of Langerhans into the renal subcapsular space of immunodeficient BALB/c.rag2(-/-).cγ(-/-) mice, previously rendered diabetic via injection of the β-cell toxin streptozocin. After the establishment of stable euglycemia, mice were reconstituted with allogeneic human peripheral blood mononuclear cells (PBMC) and the resultant alloreactive response studied. Ex vivo expanded CD25high CD4+ human Treg, which expressed FoxP3, CTLA-4, and CD62L and remained CD127low, were then cotransferred together with human PBMC and islet allografts and monitored for evidence of rejection.
  
  
  RESULTS
  Human islets transplanted into diabetic immunodeficient mice reversed diabetes but were rejected rapidly after the mice were reconstituted with allogeneic human PBMC. Cotransfer of purified, ex vivo expanded human Treg prolonged islet allograft survival resulting in the accumulation of Treg in the peripheral lymphoid tissue and suppression of proliferation and interferon-γ production by T cells. In vitro, Treg suppressed activation of signal transducers and activators of transcription and inhibited the effector differentiation of responder T cells.
  
  
  CONCLUSIONS
  Ex vivo expanded Treg retain regulatory activity in vivo, can protect a human islet allograft from rejection by suppressing signal transducers and activators of transcription activation and inhibiting T-cell differentiation, and have clinical potential as an adjunctive cellular therapy.
authors.affiliation: 1 Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK. 2 Currently, Department of Clinical Immunology and Transplantology, Medical University of Gdansk, Gdansk, Poland. 3 Address correspondence to: Professor Kathryn J. Wood, D.Phil., Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wu
authors.forename: Joanna
authors.initials: J
authors.lastname: Hester
authors.forename: Satish N
authors.initials: SN
authors.lastname: Nadig
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Piotr
authors.initials: P
authors.lastname: Trzonkowski
authors.forename: Derek
authors.initials: D
authors.lastname: Gray
authors.forename: Stephen
authors.initials: S
authors.lastname: Hughes
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D007371:Interferon-gamma
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