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Blood, 1 January 2006, Vol. 107, No. 1, pp. 381-388. Prepublished online as a Blood First Edition Paper on September 13, 2005; DOI 10.1182/blood-2005-07-2658. This Article Full Text (PDF) All Versions of this Article: 2005-07-2658v1 107/1/381    most recent Alert me when this article is cited Alert me if a correction is posted 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 Mesel-Lemoine, M. Articles by Lemoine, F. M Search for Related Content PubMed PubMed Citation Articles by Mesel-Lemoine, M. Articles by Lemoine, F. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 6, 2005 Accepted August 2, 2005 Initial depletion of regulatory T-cells: the missing solution to preserve the immune functions of T lymphocytes designed for cell-therapy Mariana Mesel-Lemoine, Mustapha Cherai, Sabine Le Gouvello, Maude Guillot, Virginie Leclercq, David Klatzmann, Veronique Thomas-Vaslin, and Francois M Lemoine* CNRS UMR 7087/UPMC, Hopital de la Pitie Salpetriere, Paris, France CNRS UMR 7087/UPMC, Hopital de la Pitie Salpetriere, Paris, France; Service de Biotherapies, Hopital de la Pitie Salpetriere, Paris, France Laboratoire d'Immunologie Biologique, Hopital Henri Mondor, Creteil, France * Corresponding author; email: francois.lemoine{at}chups.jussieu.fr. We investigated the causes of the altered functionality of T-cells cultured under conditions designed for cell and gene therapy and the strategies to prevent their defects. We first showed that human T-cells cultured for 6-days with anti-CD3 ± anti-CD28 antibodies and interleukin-2 presented a 50% decrease of their proliferative responses to allogeneic or recall antigens. Similarly, day-6 cultured murine T-cells completely lost their capacity to reject allogeneic skin grafts and to provoke graft versus host disease (GVHD) when infused into irradiated semi-allogeneic mice. Interestingly, injection of higher amount of cultured T-cells restored GVHD induction. Moreover, depletion of CD25+ cells prior to T-cell cultures can prevent these deficiencies both in mice and human. Therefore, we demonstrated that culture conditions used for T-cell therapy preferentially activated and expanded regulatory T-cells (Treg). Thus, we showed that dividing cells sorted from T-cell cultures strongly suppressed the proliferation of autologous T-cells in response to allogeneic stimulation. An increased detection of Foxp3 at mRNA and protein levels in the cultures confirmed the Treg expansion. Overall, we demonstrate that T-cell cultures promote Treg expansion over effector T-cells, leading to deleterious immune functions, and that this imbalance can be prevented by an initial depletion of CD25+ cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Noel, C. Brinster, G. Semana, and D. Bruniquel Modulation of the TCR stimulation strength can render human activated CD4+ T cells suppressive Int. Immunol., September 1, 2009; 21(9): 1025 - 1036. [Abstract] [Full Text] [PDF] A. E. B. Springs, P. W. F. Karmaus, R. B. Crawford, B. L. F. Kaplan, and N. E. Kaminski Effects of targeted deletion of cannabinoid receptors CB1 and CB2 on immune competence and sensitivity to immune modulation by {Delta}9-tetrahydrocannabinol J. Leukoc. Biol., December 1, 2008; 84(6): 1574 - 1584. [Abstract] [Full Text] [PDF] S Le Gouvello, S Bastuji-Garin, N Aloulou, H Mansour, M-T Chaumette, F Berrehar, A Seikour, A Charachon, M Karoui, K Leroy, et al. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas Gut, June 1, 2008; 57(6): 772 - 779. [Abstract] [Full Text] [PDF] A. A. Hombach, D. Kofler, A. Hombach, G. Rappl, and H. Abken Effective Proliferation of Human Regulatory T Cells Requires a Strong Costimulatory CD28 Signal That Cannot Be Substituted by IL-2 J. Immunol., December 1, 2007; 179(11): 7924 - 7931. [Abstract] [Full Text] [PDF] Y. Dang, K. L. Knutson, V. Goodell, C. dela Rosa, L. G. Salazar, D. Higgins, J. Childs, and M. L. Disis Tumor Antigen-Specific T-Cell Expansion Is Greatly Facilitated by In vivo Priming Clin. Cancer Res., March 15, 2007; 13(6): 1883 - 1891. [Abstract] [Full Text] [PDF]

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