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Clin Cancer Res. 2011 Jun 15;17(12):3969-83. doi: 10.1158/1078-0432.CCR-10-3347. Epub 2011 May 10.

Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease.

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  • 1Bone Marrow Transplant Program and the Departments of Microbiology, Pathology, and Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Abstract

PURPOSE:

Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD.

EXPERIMENTAL DESIGN:

We examined the ability of in vitro differentiated and in vivo iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied.

RESULTS:

In vitro differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and in vivo reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by in vitro exposure of iTregs to all-trans retinoic acid. In contrast, the in vivo induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD.

CONCLUSION:

Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of in vivo iTregs to prevent GVHD but has no effect on in vitro differentiated iTregs.

©2011 AACR.

PMID:
21558402
[PubMed - indexed for MEDLINE]
PMCID:
PMC3117905
Free PMC Article

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