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Blood, 22 October 2009, Vol. 114, No. 17, pp. 3693-3706. Prepublished online as a Blood First Edition Paper on August 7, 2009; DOI 10.1182/blood-2008-11-191148. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-11-191148v1 114/17/3693    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 Google Scholar Articles by Rotolo, J. A. Articles by Kolesnick, R. PubMed PubMed Citation Articles by Rotolo, J. A. Articles by Kolesnick, R. Related Collections Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease Jimmy A. Rotolo1,2, Branka Stancevic1,2, Sydney X. Lu3, Jianjun Zhang1, David Suh3, Christopher G. King3, Lucy W. Kappel3, George F. Murphy4, Chen Liu5, Zvi Fuks6, Marcel R. van den Brink3, and Richard Kolesnick1 1 Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Department of Pharmacology, Joan and Sanford I. Weill Graduate School of Medical Sciences of Cornell University, New York, NY; 3 Departments of Immunology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Department of Pathology, Brigham and Women's Hospital, Boston, MA; 5 Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville; and 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Alloreactive donor cytolytic T lymphocytes play a critical role in pathophysiology of acute graft-versus-host disease (GVHD). As GVHD progression involves tumor necrosis factor superfamily receptor activation, and as apoptotic signaling for some tumor necrosis factor superfamily receptors might involve acid sphingomyelinase (ASMase)–mediated ceramide generation, we hypothesized that ASMase deletion would ameliorate GVHD. Using clinically relevant mouse models of acute GVHD in which allogeneic bone marrow and T cells were transplanted into asmase+/+ and asmase–/– hosts, we identify host ASMase as critical for full-blown GVHD. Lack of host ASMase reduced the acute inflammatory phase of GVHD, attenuating cytokine storm, CD8+ T-cell proliferation/activation, and apoptosis of relevant graft-versus-host target cells (hepatocytes, intestinal, and skin cells). Organ injury was diminished in asmase–/– hosts, and morbidity and mortality improved at 90 days after transplantation. Resistance to cytolytic T lymphocyte–induced apoptosis was found at the target cell membrane if hepatocytes lack ASMase, as hepatocyte apoptosis required target cell ceramide generation for formation of ceramide-rich macrodomains, sites concentrating proapoptotic Fas. These studies indicate a requirement for target cell ASMase in evolution of GVHD in liver, small intestines, and skin and provide potential new targets for disease management. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Tolar, M. Eapen, P. J. Orchard, and B. R. Blazar Acid sphingomyelinase deficiency does not protect from graft-versus-host disease in transplant recipients with Niemann-Pick disease Blood, January 14, 2010; 115(2): 434 - 435. [Full Text] [PDF] R. Kolesnick, M. van den Brink, G. Heller, and J. A. Rotolo Response: Sample size and statistical comparisons of GVHD rates in pediatric Niemann-Pick disease patients Blood, January 14, 2010; 115(2): 436 - 436. [Full Text] [PDF]

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