期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 11, 期 6, 页码 1148-1157出版社
WILEY
DOI: 10.1111/j.1600-6143.2011.03558.x
关键词
Foxp3; GVHD; Rapamycin; TGF ss; Treg
资金
- Children's Cancer Research Fund
- Blood and Marrow Transplant Research Fund
- Leukemia and Lymphoma Translational Research Grant [R6029-07, R37 HL56067, P01 AI056299, NCI P01 CA067493, NHLBI N01HB037164]
- JDRF Collaborative Centers for Cell Therapy
- JDRF Center on Cord Blood Therapies for Type 1 Diabetes
- NIH [P30 CA77598]
Adoptive transfer of thymus-derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft-versus-host disease (GVHD). TGF ss 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 TGF ss induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGF ss-dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25-45RA+) T cells. Rapa/TGF ss iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL-2, IFN gamma or IL-17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGF ss induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average similar to 240 x 109 (range similar to 70-560 x 109) iTregs from CD4+25- T cells in < 2 weeks of culture. Most importantly, Rapa/TGF ss iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases.
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