| First Author | Rotolo JA | Year | 2009 |
| Journal | Blood | Volume | 114 |
| Issue | 17 | Pages | 3693-706 |
| PubMed ID | 19666872 | Mgi Jnum | J:154080 |
| Mgi Id | MGI:4367174 | Doi | 10.1182/blood-2008-11-191148 |
| Citation | Rotolo JA, et al. (2009) Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease. Blood 114(17):3693-706 |
| abstractText | 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. |
