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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-07-2076. This Article Full Text (PDF) All Versions of this Article: 2002-07-2076v1 101/8/3325    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 Guillot, C. Articles by Anegon, I. Search for Related Content PubMed PubMed Citation Articles by Guillot, C. Articles by Anegon, I. Social Bookmarking                   What's this? Submitted July 15, 2002 Accepted December 10, 2002 Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig Cecile Guillot, Severine Menoret, Carole Guillonneau, Cecile Braudeau, Maria G Castro, Pedro Lowenstein, and Ignacio Anegon* Unite 437, Institut National de la Sante et de la Recherche Medicale (INSERM) et Institut de Transplantation et Recherche en Transplantation (ITERT), Nantes, France Gene Therapeutics Research Institute, UCLA Cedars-Sinai Medical Center, Los Angeles, CA, USA * Corresponding author; email: ianegon{at}nantes.inserm.fr. Costimulatory blockade using CTLA4Ig efficiently down-regulates immune responses in animal models and is currently being used in autoimmune and transplantation clinical trials, but the precise cellular and molecular mechanisms involved remain unclear. Rats transplanted with allogeneic hearts and treated with adenoviruses coding for CTLA4Ig show long-term allograft survival. The immune mechanisms regulating induction of long-term allograft acceptance were analyzed in splenocytes using mixed leukocyte reactions (MLRs). MLRs of splenocytes but not purified T cells, from CTLA4Ig-treated rats showed > 75% inhibition compared to controls. Splenocytes from CTLA4Ig-treated rats inhibited proliferation of naive and allogeneically primed splenocytes or T cells. MLRs suppression was dependent on soluble secreted product(s). Production of soluble inhibitory product(s) was triggered by a donor antigen-specific stimulation and inhibited proliferation in an antigen non-specific manner. CTLA4Ig levels in the culture supernatant were undetectable and neither IL-10, TGF1, IL-4, nor IL-13 were responsible for suppression of MLRs. Inhibition of NO production or addition of IL-2 could not restore proliferation independently but the combined treatment synergistically induced proliferation comparable to controls. Stimulation of APCs using TNF-related activation-induced cytokine (TRANCE) or CD40L and addition of IL-2 normalized MLRs of CTLA4Ig-treated splenocytes. Finally, dendritic cells (DCs), but not T cells, from CTLA4Ig-treated rats inhibited naive MLRs. Altogether, these results provide evidence that after in vivo CTLA4Ig treatment, splenocytes and in particular DCs, can inhibit alloantigen-induced proliferative responses through secretion of inhibitory products, thus promoting alloantigen-specific tolerance in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A.-S. Dugast, T. Haudebourg, F. Coulon, M. Heslan, F. Haspot, N. Poirier, R. Vuillefroy de Silly, C. Usal, H. Smit, B. Martinet, et al. Myeloid-Derived Suppressor Cells Accumulate in Kidney Allograft Tolerance and Specifically Suppress Effector T Cell Expansion J. Immunol., June 15, 2008; 180(12): 7898 - 7906. [Abstract] [Full Text] [PDF] C. Guillonneau, C. Seveno, A.-S. Dugast, X.-L. Li, K. Renaudin, F. Haspot, C. Usal, J. Veziers, I. Anegon, and B. Vanhove Anti-CD28 Antibodies Modify Regulatory Mechanisms and Reinforce Tolerance in CD40Ig-Treated Heart Allograft Recipients J. Immunol., December 15, 2007; 179(12): 8164 - 8171. [Abstract] [Full Text] [PDF] D. S. Pouniotis, O. Proudfoot, V. Bogdanoska, K. Scalzo, S. Kovacevic, R. L. Coppel, and M. Plebanski Selectively Impaired CD8+ but Not CD4+ T Cell Cycle Arrest during Priming as a Consequence of Dendritic Cell Interaction with Plasmodium-Infected Red Cells J. Immunol., September 15, 2005; 175(6): 3525 - 3533. [Abstract] [Full Text] [PDF] S. Nierkens, M. Aalbers, M. Bol, R. Bleumink, P. van Kooten, L. Boon, and R. Pieters Differential Requirement for CD28/CTLA-4-CD80/CD86 Interactions in Drug-Induced Type 1 and Type 2 Immune Responses to Trinitrophenyl-Ovalbumin J. Immunol., September 15, 2005; 175(6): 3707 - 3714. [Abstract] [Full Text] [PDF] C. Vasu, B. S. Prabhakar, and M. J. Holterman Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity J. Immunol., August 15, 2004; 173(4): 2866 - 2876. [Abstract] [Full Text] [PDF]

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