International Immunology Advance Access originally published online on January 13, 2006
International Immunology 2006 18(2):279-289; doi:10.1093/intimm/dxh368
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Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient
1 Division of Rheumatology and Immunology, Department of Medicine, 2011 Zonal Avenue, HMR 711 and 2 Department of Cardiothoracic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Correspondence to: D. A. Horwitz; E-mail: dhorwitz{at}usc.edu
Certain CD4+CD25+ T cells can induce and maintain T-cell non-responsiveness to donor alloantigens and have therapeutic potential in solid organ transplantation. Peripheral CD4+CD25– cells alloactivated with IL-2 and transforming growth factor ß (TGF-ß) ex vivo express the transcription factor FoxP3, and become potent antigen-specific CD4+CD25– suppressor cells. Here we report that the transfer of TGF-ß-induced regulatory CD4+ and CD8+ T cells (Tregs) co-incident with transplantation of a histoincompatible heart resulted in extended allograft survival. To account for this result, we injected non-transplanted mice with a single dose of CD4+ and CD8+ Tregs and transferred donor cells every 2 weeks to mimic the continuous stimulation of a transplant. We observed increased splenic CD4+CD25+ cells that were of recipient origin. These cells rendered the animals non-responsive to donor alloantigens by an antigen-specific and cytokine-dependent mechanism of action. Both the increased number of CD4+CD25+ cells and their tolerogenic effect were dependent on continued donor antigen boosting. Thus, Tregs generated ex vivo can act like a vaccine that generates host suppressor cells with the potential to protect MHC-mismatched organ grafts from rejection.
Keywords: cardiac allografts, TGF-ß, tolerance, transplantation, regulatory T cells
Transmitting editor: W. Strober
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