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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-11-3370. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3370v1 101/11/4457    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 Hackstein, H. Articles by Thomson, A. W. Search for Related Content PubMed PubMed Citation Articles by Hackstein, H. Articles by Thomson, A. W. Related Collections Immunobiology Transplantation Gene Expression Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2003, Vol. 101, No. 11, pp. 4457-4463 IMMUNOBIOLOGY Rapamycin inhibits IL-4—induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo Holger Hackstein, Timucin Taner, Alan F. Zahorchak, Adrian E. Morelli, Alison J. Logar, Andre Gessner, and Angus W. Thomson From the Thomas E. Starzl Transplantation Institute and Department of Surgery, and Department of Immunology, University of Pittsburgh, PA; Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University, Giessen, Germany; and Institute for Clinical Microbiology and Immunology, University Erlangen, Erlangen, Germany. Rapamycin (RAPA) is a potent immunosuppressive macrolide hitherto believed to mediate its action primarily via suppression of lymphocyte responses to interleukin 2 (IL-2) and other growth factors. We show here that this view is incomplete and provide evidence that RAPA suppresses the functional activation of dendritic cells (DCs) both in vitro and in vivo. In vitro, RAPA inhibits IL-4—dependent maturation and T-cell stimulatory activity of murine bone marrow—derived DCs. These effects are associated with posttranscriptional down-regulation of both subunits of the IL-4 receptor complex (CD124, CD132) and are mediated via binding of RAPA to its intracellular receptor FK506-binding protein 12 (FKBP12). In vivo, RAPA impairs steady-state DC generation and fms-like tyrosine 3 kinase ligand (Flt3L)—induced DC mobilization. In addition, in vivo administration of RAPA impairs DC costimulatory molecule up-regulation, production of proinflammatory cytokines, and T-cell allostimulatory capacity. These novel findings have implications for RAPA-based therapy of chronic DC-triggered autoimmune diseases, transplant rejection, and hematologic malignancies with activating Flt3 mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. E. Anderson, D. J. Swan, B. L. Sayers, R. A. Harry, A. M. Patterson, A. von Delwig, J. H. Robinson, J. D. Isaacs, and C. M. U. Hilkens LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells J. Leukoc. Biol., February 1, 2009; 85(2): 243 - 250. [Abstract] [Full Text] [PDF] W. Zang, M. Lin, S. Kalache, N. Zhang, B. Kruger, A. M. Waaga-Gasser, M. Grimm, W. Hancock, P. Heeger, B. Schroppel, et al. Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide J. Immunol., December 1, 2008; 181(11): 7499 - 7506. [Abstract] [Full Text] [PDF] A W Thomson and P D Robbins Tolerogenic dendritic cells for autoimmune disease and transplantation Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii90 - iii96. [Abstract] [Full Text] [PDF] W. Reichardt, C. Durr, D. von Elverfeldt, E. Juttner, U. V. Gerlach, M. Yamada, B. Smith, R. S. Negrin, and R. Zeiser Impact of Mammalian Target of Rapamycin Inhibition on Lymphoid Homing and Tolerogenic Function of Nanoparticle-Labeled Dendritic Cells following Allogeneic Hematopoietic Cell Transplantation J. Immunol., October 1, 2008; 181(7): 4770 - 4779. [Abstract] [Full Text] [PDF] M. Ohtani, S. Nagai, S. Kondo, S. Mizuno, K. Nakamura, M. Tanabe, T. Takeuchi, S. Matsuda, and S. Koyasu Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells Blood, August 1, 2008; 112(3): 635 - 643. [Abstract] [Full Text] [PDF] H. R. Turnquist, T. L. Sumpter, A. Tsung, A. F. Zahorchak, A. Nakao, G. J. Nau, F. Y. Liew, D. A. Geller, and A. W. Thomson IL-1{beta}-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells J. Immunol., July 1, 2008; 181(1): 62 - 72. [Abstract] [Full Text] [PDF] E. Coutanceau, J. Decalf, A. Martino, A. Babon, N. Winter, S. T. Cole, M. L. Albert, and C. Demangel Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone J. Exp. Med., June 11, 2007; 204(6): 1395 - 1403. [Abstract] [Full Text] [PDF] H. R. Turnquist, G. Raimondi, A. F. Zahorchak, R. T. Fischer, Z. Wang, and A. W. Thomson Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance J. Immunol., June 1, 2007; 178(11): 7018 - 7031. [Abstract] [Full Text] [PDF] C. Cutler, S. Li, V. T. Ho, J. Koreth, E. Alyea, R. J. Soiffer, and J. H. 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Hackstein Cutting Edge: Sanglifehrin A, a Novel Cyclophilin-Binding Immunosuppressant Blocks Bioactive IL-12 Production by Human Dendritic Cells J. Immunol., July 15, 2003; 171(2): 542 - 546. [Abstract] [Full Text] [PDF]

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