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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1696-1702. Prepublished online as a Blood First Edition Paper on November 1, 2005; DOI 10.1182/blood-2005-07-2800. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-2800v1 107/4/1696    most recent 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 de Kleer, I. Articles by Prakken, B. Search for Related Content PubMed PubMed Citation Articles by de Kleer, I. Articles by Prakken, B. Related Collections Transplantation Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network Ismé de Kleer, Bas Vastert, Mark Klein, Gijs Teklenburg, Ger Arkesteijn, Gisella Puga Yung, Salvo Albani, Wietse Kuis, Nico Wulffraat, and Berent Prakken From the University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Pediatric Immunology, Utrecht, The Netherlands; the University of California, San Diego, CA; and the Faculty of Veterinary Medicine, Utrecht University, Division of Immunology, Utrecht, The Netherlands. Despite a rapidly accumulating clinical experience with autologous stem cell transplantation (ASCT) as a treatment for severe refractory autoimmune disease, data on the mechanisms by which ASCT induces immune tolerance are still very scarce. In this study it is shown that ASCT restores immunologic self-tolerance in juvenile idiopathic arthritis (JIA) via 2 mechanisms. First, ASCT induces a restoration of the frequency of FoxP3 expressing CD4+CD25bright regulatory T cells (Tregs) from severely reduced numbers before ASCT to normal levels after ASCT. This recovery is due to a preferential homeostatic expansion of CD4+CD25+ Tregs during the lymphopenic phase of immunereconstitution, as measured by Ki67 and CD44 expression, and to a renewed thymopoiesis of naive mRNA FoxP3 expressing CD4+CD25+ Tregs after ASCT. Second, using artificial antigen-presenting cells to specifically isolate self-reactive T cells, we demonstrate that ASCT induces autoimmune cells to deviate from a proinflammatory phenotype (mRNA interferon- [IFN-] and T-bet high) to a tolerant phenotype (mRNA interleukin-10 [IL-10] and GATA-3 high). These data are the first to demonstrate the qualitative immunologic changes that are responsible for the induction of immune tolerance by ASCT for JIA: the restoration of the CD4+CD25+ immune regulatory network and reprogramming of autoreactive T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. D. Isaacs Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future Rheumatology, May 25, 2008; (2008) ken163v1. [Abstract] [Full Text] [PDF] S. T. A. Roord, W. de Jager, L. Boon, N. Wulffraat, A. Martens, B. Prakken, and F. van Wijk Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+CD25+Foxp3+ regulatory T cells Blood, May 15, 2008; 111(10): 5233 - 5241. [Abstract] [Full Text] [PDF] T. Bohgaki, T. Atsumi, and T. Koike Multiple Autoimmune Diseases after Autologous Stem-Cell Transplantation N. Engl. J. Med., December 27, 2007; 357(26): 2734 - 2736. [Full Text] [PDF] F. GUALANDI, B. BRUNO, M.T. VAN LINT, S. LUCHETTI, A. UCCELLI, E. CAPELLO, G.L. MANCARDI, A. BACIGALUPO, and A. MARMONT Autologous Stem Cell Transplantation for Severe Autoimmune Diseases: A 10-Year Experience Ann. N.Y. Acad. Sci., September 1, 2007; 1110(1): 455 - 464. [Abstract] [Full Text] [PDF] F. Behrens, A. Himsel, S. Rehart, J. Stanczyk, B. Beutel, S. Y Zimmermann, U. Koehl, B. Moller, S. Gay, J. P Kaltwasser, et al. Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis Ann Rheum Dis, September 1, 2007; 66(9): 1151 - 1156. [Abstract] [Full Text] [PDF] R. A. Nash, P. A. McSweeney, L. J. Crofford, M. Abidi, C.-S. Chen, J. D. Godwin, T. A. Gooley, L. Holmberg, G. Henstorf, C. F. LeMaistre, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study Blood, August 15, 2007; 110(4): 1388 - 1396. [Abstract] [Full Text] [PDF] L. Weng, J. Dyson, and F. Dazzi Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment PNAS, May 15, 2007; 104(20): 8415 - 8420. [Abstract] [Full Text] [PDF] P. Hoffmann, R. Eder, T. J. Boeld, K. Doser, B. Piseshka, R. Andreesen, and M. Edinger Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion Blood, December 15, 2006; 108(13): 4260 - 4267. [Abstract] [Full Text] [PDF] J. M. van Laar and A. Tyndall Adult stem cells in the treatment of autoimmune diseases Rheumatology, October 1, 2006; 45(10): 1187 - 1193. [Abstract] [Full Text] [PDF]

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