Dataset Information

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

ABSTRACT: 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.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.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-?. 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.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.

SUBMITTER: Beres A

PROVIDER: S-EPMC3117905 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Beres Amy A Komorowski Richard R Mihara Masahiko M Drobyski William R WR

Clinical cancer research : an official journal of the American Association for Cancer Research 20110510 12

<h4>Purpose</h4>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.<h4>Experimental design</h4>We exami ...[more]

PMID: 21558402

Similar Datasets

Project description:Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3-4 months) and older (14-18 months) DCreg were generated using GM-CSF, IL-10, and TGF?. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c?C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may utilize to induce and maintain tolerance to GVHD.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets