Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model

Douglas C. Wu, Joanna Hester, Satish N. Nadig, Wei Zhang, Piotr Trzonkowski, Derek Gray, Stephen Hughes, Paul Johnson, Kathryn J. Wood*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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 CD25highCD4+ 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.

Original languageEnglish (US)
Pages (from-to)707-716
Number of pages10
JournalTransplantation
Volume96
Issue number8
DOIs
StatePublished - Oct 27 2013
Externally publishedYes

Keywords

  • Allograft
  • Cellular therapy
  • Humanized mouse model
  • Islet transplantation
  • Regulatory T cells

ASJC Scopus subject areas

  • Transplantation

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