Faculty Collaboration Database

Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease. Clin Cancer Res 2011 Jun 15;17(12):3969-83

Date

05/12/2011

Pubmed ID

21558402

Pubmed Central ID

PMC3117905

DOI

10.1158/1078-0432.CCR-10-3347

Scopus ID

2-s2.0-79959268660 (requires institutional sign-in at Scopus site)   81 Citations

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.

Author List

Beres A, Komorowski R, Mihara M, Drobyski WR

Author

William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Blocking
Bone Marrow Transplantation
Forkhead Transcription Factors
Gene Expression Regulation
Graft vs Host Disease
Immunologic Factors
Inflammation
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Phenotype
Receptors, Interleukin-6
Signal Transduction
T-Lymphocytes, Regulatory
Tretinoin