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Am J Transplant. 2011 Jun;11(6):1148-57. doi: 10.1111/j.1600-6143.2011.03558.x. Epub 2011 May 12.

Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease.

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  • 1Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, USA. hippe002@umn.edu

Abstract

Adoptive transfer of thymus-derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft-versus-host disease (GVHD). TGFß induces Foxp3 expression and suppressive function in stimulated murine CD4+25- T cells, and these induced Treg (iTregs), like nTreg, suppress auto- and allo-reactivity in vivo. However, while TGFß induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGFß-dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25-45RA+) T cells. Rapa/TGFß iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL-2, IFNγ or IL-17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGFß induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ~240 × 10⁹ (range ~ 70-560 × 10⁹) iTregs from CD4+25- T cells in ≤ 2 weeks of culture. Most importantly, Rapa/TGFß iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases.

©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

PMID:
21564534
[PubMed - indexed for MEDLINE]
PMCID:
PMC3552455
Free PMC Article
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