Ex vivo-expanded natural CD4+CD25+ regulatory T cells synergize with host T-cell depletion to promote long-term survival of allografts

G. Xia*, J. He, J. R. Leventhal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Foxp3+CD4+CD25+ natural regulatory T (nTreg) cells have been shown in immunodeficient mice to suppress allograft rejection after adoptive cotransfer. We hypothesized that immunotherapy using ex vivo-expanded nTreg could suppress allograft rejection in wild-type mice. Donor alloantigen (alloAg) specificity of naive splenic nTreg was enriched in vitro by culturing with anti-CD3/CD28-coated Dynabeads plus bone marrow-derived dendritic cells (BM-DC) in the presence of interleukin (IL)-2 or IL-2 plus transforming growth factor (TGF)-β. On average, 96.2% fresh CD4+CD25+ nT reg were intracellular Foxp3+. By d+20 in culture, 6.4% nTreg were Foxp3+ following expansion with IL-2 alone, and 14.4% or 19.7% nTreg were Foxp3+ when expanded with IL-2 plus 0.5 or 2.5 ng/mL TGF-β, respectively. In vitro, alloAg-enriched, TGF-β/IL-2-conditioned nTreg exerted stronger donor alloAg-specific suppression than cells with IL-2 alone in mixed lymphocyte reaction (MLR) assays. In vivo, alloAg-enriched, TGF-β/IL-2-conditioned nTreg expressed high-level Foxp3 following infusion, effectively overcame acute rejection and induced long-term survival of donor but not third-party heart allografts in peritransplant host T-cell-depleted mice. Long-term surviving allografts were noted to possess Foxp3+ graft-infiltrating cells of exogenous and endogenous origins. In conjunction with transient host T-cell depletion, therapeutic use of ex vivo-expanded nTreg may be a practical means of preventing acute allograft rejection.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalAmerican Journal of Transplantation
Volume8
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Anti-Thy1 model
  • Cell therapy
  • Immunoregulatory T lymphocytes
  • Induction of graft tolerance
  • TGF-ß

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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