title: Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient.
abstract: 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 beta (TGF-beta) ex vivo express the transcription factor FoxP3, and become potent antigen-specific CD4+CD25- suppressor cells. Here we report that the transfer of TGF-beta-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.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, 2011 Zonal Avenue, HMR 711.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.forename: Lingzhong
authors.initials: L
authors.lastname: Meng
authors.forename: Ju Hua
authors.initials: JH
authors.lastname: Wang
authors.forename: Meguru
authors.initials: M
authors.lastname: Watanabe
authors.forename: Mark L
authors.initials: ML
authors.lastname: Barr
authors.forename: Donald V
authors.initials: DV
authors.lastname: Cramer
authors.forename: J Dixon
authors.initials: JD
authors.lastname: Gray
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D000939:Epitopes; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015375:Receptors, Interleukin-2; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation*
chemical_list: D000939:Epitopes; D015375:Receptors, Interleukin-2