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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-09-2798. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-09-2798v1 101/12/5076    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 Chen, Z.-m. Articles by Blazar, B. R. Search for Related Content PubMed PubMed Citation Articles by Chen, Z.-m. Articles by Blazar, B. R. Related Collections Immunobiology Transplantation Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 5076-5083 TRANSPLANTATION IL-10 and TGF- induce alloreactive CD4+CD25– T cells to acquire regulatory cell function Zong-ming Chen, Matthew J. O'Shaughnessy, Irene Gramaglia, Angela Panoskaltsis-Mortari, William J. Murphy, Satwant Narula, Maria G. Roncarolo, and Bruce R. Blazar From the University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN; Science Applications International Corporation (SAIC)–Frederick and the Laboratory of Leukocyte Biology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD; Schering-Plough Research Institute, Kenilworth, NJ; and San Raffaele-Telethon Institute (Hospital San Raffaele-Telethon Institute for Gene Therapy [HSR-TIGET]), Milan, Italy. We previously reported that interleukin-10 (IL-10) and transforming growth factor (TGF)– treatment of primary mixed lymphocyte reaction (MLR) cultures resulted in secondary alloantigen-specific hyporesponsiveness and protection from graft-versus-host disease (GVHD) lethality. Here, we report that CD4+ T cells recovered from the IL-10– and TGF-–treated primary MLR cultures have immunoregulatory function. Tolerized cells significantly inhibited proliferation of naive alloreactive CD4+ T cells in a primary MLR. Inhibition of the naive alloresponse was observed with as few as 1 tolerized cell to 10 naive responder cells. Tolerized cells were able to significantly reduce GVHD lethality when injected with naive alloreactive CD4+ T cells into major histocombatibility class (MHC) II disparate recipients. Rigorous CD25 depletion of the primary MLR had no effect on generation of a regulatory capacity, suggesting that the regulatory cells likely originated from CD4+CD25– T cells. Immune suppression was mediated independently of IL-10 and TGF- production, as neutralizing antibodies for IL-10, IL-10R, and TGF- were unable to revert suppression, and IL-10– deficient CD4+ T cells were able to mediate in vitro and in vivo suppression. The generation of immunoregulatory cells from a CD4+CD25– population during tolerization with IL-10 and TGF- provides an additional mechanism to prevent GVHD lethality by T cells that may escape full tolerance induction. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Howie, K. F. Nolan, S. Daley, E. Butterfield, E. Adams, H. Garcia-Rueda, C. Thompson, N. J. Saunders, S. P. Cobbold, Y. Tone, et al. MS4A4B Is a GITR-Associated Membrane Adapter, Expressed by Regulatory T Cells, Which Modulates T Cell Activation J. Immunol., October 1, 2009; 183(7): 4197 - 4204. [Abstract] [Full Text] [PDF] C. Vogtenhuber, M. J. O'Shaughnessy, D. A. A. Vignali, and B. R. Blazar Outgrowth of CD4low/negCD25+ T Cells with Suppressor Function in CD4+CD25+ T Cell Cultures upon Polyclonal Stimulation Ex Vivo J. Immunol., December 15, 2008; 181(12): 8767 - 8775. [Abstract] [Full Text] [PDF] E. Godebu, D. Summers-Torres, M. M. 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