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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Taylor, P. A. Articles by Blazar, B. R. Search for Related Content PubMed PubMed Citation Articles by Taylor, P. A. Articles by Blazar, B. R. Related Collections Immunobiology Transplantation Plenary Papers Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2002, Vol. 99, No. 10, pp. 3493-3499 PLENARY PAPER The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality Patricia A. Taylor, Christopher J. Lees, and Bruce R. Blazar From the University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis. Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and the prevention of autoimmunity. Recently, CD4+CD25+ cells have been shown to be required for the ex vivo induction of tolerance to alloantigen via costimulatory blockade and to inhibit allogeneic skin graft rejection. Data presented here demonstrate that CD4+CD25+ cells play an important role in graft-versus-host disease (GVHD) generation. Depletion of CD4+CD25+ cells from the donor T-cell inoculum or in vivo CD25-depletion of the recipient before transplantation resulted in increased GVHD mediated by CD4+ or whole T cells in several strain combinations irrespective of the total body irradiation conditioning regime. The infusion of freshly purified donor CD4+CD25+ cells modestly inhibited GVHD when administered in equal numbers with whole CD4+ cells. Because CD4+CD25+ cells only account for 5% to 10% of the total CD4+ population, the administration of high numbers of fresh donor CD4+CD25+ cells may not be clinically practical. However, we found that large numbers of CD4+CD25+ cells can be obtained by ex vivo activation and expansion. Cultured CD4+CD25+ cells, administered in equal numbers with CD4+ T cells or CD25-depleted whole T cells, resulted in significant inhibition of rapidly lethal GVHD. To our knowledge, this study is the first to demonstrate that activated, cultured CD4+CD25+ cells can offer substantial protection in a relevant in vivo animal model of disease. These data have important ramifications for clinical bone marrow and solid organ transplantation. CD4+CD25+ cells warrant consideration as an exciting new modality of cellular therapy for the inhibition of undesirable autologous and allogeneic responses. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Matthews, Z. Lim, B. Afzali, L. Pearce, A. Abdallah, S. Kordasti, A. Pagliuca, G. Lombardi, J. A. Madrigal, G. J. Mufti, et al. Imbalance of effector and regulatory CD4 T cells is associated with graft-versus-host disease after hematopoietic stem cell transplantation using a reduced intensity conditioning regimen and alemtuzumab Haematologica, July 1, 2009; 94(7): 956 - 966. [Abstract] [Full Text] [PDF] B. Blanco, J. A. Perez-Simon, L. I. Sanchez-Abarca, T. Caballero-Velazquez, S. Gutierrez-Cossio, P. Hernandez-Campo, M. Diez-Campelo, C. Herrero-Sanchez, C. Rodriguez-Serrano, C. Santamaria, et al. 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Zou Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals Cancer Res., November 15, 2004; 64(22): 8451 - 8455. [Abstract] [Full Text] [PDF] E. A. Moseman, X. Liang, A. J. Dawson, A. Panoskaltsis-Mortari, A. M. Krieg, Y.-J. Liu, B. R. Blazar, and W. Chen Human Plasmacytoid Dendritic Cells Activated by CpG Oligodeoxynucleotides Induce the Generation of CD4+CD25+ Regulatory T Cells J. Immunol., October 1, 2004; 173(7): 4433 - 4442. [Abstract] [Full Text] [PDF] Y. Miura, C. J. Thoburn, E. C. Bright, M. L. Phelps, T. Shin, E. C. Matsui, W. H. Matsui, S. Arai, E. J. Fuchs, G. B. Vogelsang, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease Blood, October 1, 2004; 104(7): 2187 - 2193. [Abstract] [Full Text] [PDF] K. V. Komanduri and R. E. Champlin GVHD therapy: the best-laid schemes... Blood, September 1, 2004; 104(5): 1240 - 1241. [Full Text] [PDF] B. E. Anderson, J. M. McNiff, C. Matte, I. Athanasiadis, W. D. Shlomchik, and M. J. Shlomchik Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease Blood, September 1, 2004; 104(5): 1565 - 1573. [Abstract] [Full Text] [PDF] G. Zheng, B. Wang, and A. Chen The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cells J. Immunol., August 15, 2004; 173(4): 2428 - 2434. [Abstract] [Full Text] [PDF] E. Nishimura, T. Sakihama, R. Setoguchi, K. Tanaka, and S. Sakaguchi Induction of antigen-specific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells Int. Immunol., August 1, 2004; 16(8): 1189 - 1201. [Abstract] [Full Text] [PDF] P. Hoffmann, R. Eder, L. A. Kunz-Schughart, R. Andreesen, and M. Edinger Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells Blood, August 1, 2004; 104(3): 895 - 903. [Abstract] [Full Text] [PDF] W. R. Godfrey, Y. G. Ge, D. J. Spoden, B. L. Levine, C. H. June, B. R. Blazar, and S. B. Porter In vitro-expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures Blood, July 15, 2004; 104(2): 453 - 461. [Abstract] [Full Text] [PDF] L. Graca, A. Le Moine, C.-Y. Lin, P. J. Fairchild, S. P. Cobbold, and H. Waldmann Donor-specific transplantation tolerance: The paradoxical behavior of CD4+CD25+ T cells PNAS, July 6, 2004; 101(27): 10122 - 10126. [Abstract] [Full Text] [PDF] Q. Tang, K. J. Henriksen, M. Bi, E. B. Finger, G. Szot, J. Ye, E. L. Masteller, H. McDevitt, M. Bonyhadi, and J. A. Bluestone In Vitro-expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes J. Exp. Med., June 7, 2004; 199(11): 1455 - 1465. [Abstract] [Full Text] [PDF] A. Fietta, F. Meloni, M. Stanzani, and K. V. Komanduri Only genuine CD4+CD25+ Tregs may be friends or foes Blood, June 1, 2004; 103(11): 4369 - 4370. [Full Text] [PDF] O. Joffre, N. Gorsse, P. Romagnoli, D. Hudrisier, and J. P. M. van Meerwijk Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes Blood, June 1, 2004; 103(11): 4216 - 4221. [Abstract] [Full Text] [PDF] F. J. Clark, R. Gregg, K. Piper, D. Dunnion, L. Freeman, M. Griffiths, G. Begum, P. Mahendra, C. Craddock, P. Moss, et al. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells Blood, March 15, 2004; 103(6): 2410 - 2416. [Abstract] [Full Text] [PDF] B. J. Chen, X. Cui, G. D. Sempowski, C. Liu, and N. J. Chao Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease Blood, February 15, 2004; 103(4): 1534 - 1541. [Abstract] [Full Text] [PDF] L. A. Stephens, A. N. Barclay, and D. Mason Phenotypic characterization of regulatory CD4+CD25+ T cells in rats Int. Immunol., February 1, 2004; 16(2): 365 - 375. [Abstract] [Full Text] [PDF] S. G. Zheng, J. H. Wang, M. N. Koss, F. Quismorio Jr., J. D. Gray, and D. A. Horwitz CD4+ and CD8+ Regulatory T Cells Generated Ex Vivo with IL-2 and TGF-{beta} Suppress a Stimulatory Graft-versus-Host Disease with a Lupus-Like Syndrome J. Immunol., February 1, 2004; 172(3): 1531 - 1539. [Abstract] [Full Text] [PDF] S. R. Solomon CD4+CD25+ T cells: friends or foes? Blood, February 1, 2004; 103(3): 757 - 757. [Full Text] [PDF] M. Stanzani, S. L. R. Martins, R. M. Saliba, L. S. St. John, S. Bryan, D. Couriel, J. McMannis, R. E. Champlin, J. J. Molldrem, and K. V. Komanduri CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans Blood, February 1, 2004; 103(3): 1140 - 1146. [Abstract] [Full Text] [PDF] P. A. Taylor, C. J. Lees, S. Fournier, J. P. Allison, A. H. Sharpe, and B. R. Blazar B7 Expression on T Cells Down-Regulates Immune Responses through CTLA-4 Ligation via R-T Interactions J. Immunol., January 1, 2004; 172(1): 34 - 39. 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Gray The role of the combination of IL-2 and TGF-{beta} or IL-10 in the generation and function of CD4+ CD25+ and CD8+regulatory T cell subsets J. Leukoc. Biol., October 1, 2003; 74(4): 471 - 478. [Abstract] [Full Text] [PDF] S. Fisson, G. Darrasse-Jeze, E. Litvinova, F. Septier, D. Klatzmann, R. Liblau, and B. L. Salomon Continuous Activation of Autoreactive CD4+ CD25+ Regulatory T Cells in the Steady State J. Exp. Med., September 2, 2003; 198(5): 737 - 746. [Abstract] [Full Text] [PDF]

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