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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4588-4598. Prepublished online as a Blood First Edition Paper on September 7, 2007; DOI 10.1182/blood-2007-08-106005. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-08-106005v1 110/13/4588    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 Zeiser, R. Articles by Negrin, R. S. Search for Related Content PubMed PubMed Citation Articles by Zeiser, R. Articles by Negrin, R. S. Related Collections Transplantation Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity Robert Zeiser1,2, Sawsan Youssef3, Jeanette Baker1, Neeraja Kambham4, Lawrence Steinman3, and Robert S. Negrin1 1 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; 2 Division of Hematology and Oncology, Department of Medicine, Albert Ludwig University Freiburg, Freiburg, Germany; 3 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA; and 4 Department of Pathology; Stanford University School of Medicine, Stanford, CA We investigated whether atorvastatin (AT) was capable of protecting animals from acute graft-versus-host disease (aGVHD) across major histocompatibility complex (MHC) mismatch barriers. AT treatment of the donor induced a Th-2 cytokine profile in the adoptively transferred T cells and reduced their in vivo expansion, which translated into significantly reduced aGVHD lethality. Host treatment down-regulated costimulatory molecules and MHC class II expression on recipient antigen-presenting cells (APCs) and enhanced the protective statin effect, without impacting graft-versus-leukemia (GVL) activity. The AT effect was partially reversed in STAT6–/– donors and abrogated by L-mevalonate, indicating the relevance of STAT6 signaling and the L-mevalonate pathway for AT-mediated aGVHD protection. AT reduced prenylation levels of GTPases, abolished T-bet expression, and increased c-MAF and GATA-3 protein in vivo. Thus, AT has significant protective impact on aGVHD lethality by Th-2 polarization and inhibition of an uncontrolled Th-1 response while maintaining GVL activity, which is of great clinical relevance given the modest toxicity profile of AT. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Statins inhibit human APC function: implications for the treatment of GVHD Alexander Shimabukuro-Vornhagen, Tanja Liebig, and Michael von Bergwelt-Baildon Blood 2008 112: 1544-1545. [Full Text] [PDF] This article has been cited by other articles: A. Shimabukuro-Vornhagen, T. Liebig, and M. von Bergwelt-Baildon Statins inhibit human APC function: implications for the treatment of GVHD Blood, August 15, 2008; 112(4): 1544 - 1545. [Full Text] [PDF] M. Hamadani, F. T. Awan, and S. M. Devine The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation Blood, April 1, 2008; 111(7): 3901 - 3902. [Full Text] [PDF]

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