Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease Journal Article


Authors: Rotolo, J. A.; Stancevic, B.; Lu, S. X.; Zhang, J.; Suh, D.; King, C. G.; Kappel, L. W.; Murphy, G. F.; Liu, C.; Fuks, Z.; Van Den Brink, M. R.; Kolesnick, R.
Article Title: Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease
Abstract: 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<sup>+/+</sup> and asmase<sup>-/-</sup> 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<sup>+</sup> T-cell proliferation/activation, and apoptosis of relevant graft-versus-host target cells (hepatocytes, intestinal, and skin cells). Organ injury was diminished in asmase<sup>-/-</sup> 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. © 2009 by The American Society of Hematology.
Keywords: controlled study; survival rate; gene deletion; nonhuman; cd8+ t lymphocyte; lymphocyte proliferation; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; animal tissue; hepatocytes; apoptosis; fas antigen; animal experiment; animal model; mice, scid; mice, inbred c57bl; skin; disease model; liver; lymphocyte activation; cytokines; acute graft versus host disease; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; cell membrane; allogeneic hematopoietic stem cell transplantation; cytokine production; target cell; interferon-gamma; liver cell; disease models, animal; bone marrow transplantation; graft vs host disease; intestine, small; intestine cell; t lymphocyte activation; immunopathogenesis; skin cell; ceramide; ceramides; sphingomyelin phosphodiesterase; organ injury; transplantation tolerance; mice, inbred mrl lpr
Journal Title: Blood
Volume: 114
Issue: 17
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2009-01-01
Start Page: 3693
End Page: 3706
Language: English
DOI: 10.1182/blood-2008-11-191148
PUBMED: 19666872
PROVIDER: scopus
PMCID: PMC2766684
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: BLOOA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Zvi Fuks
    286 Fuks
  2. Jianjun Zhang
    7 Zhang
  3. Richard N Kolesnick
    224 Kolesnick
  4. Jimmy A Rotolo
    31 Rotolo
  5. Christopher King
    29 King
  6. Sydney X Lu
    48 Lu
  7. David Suh
    41 Suh
  8. Lucy Willis
    27 Willis