The Role of p53 and Fas in a Model of Acute Murine Graft-versus-Host Disease

• Published in: The Journal of immunology (1950) 2005-02, Vol.174 (3), p.1291-1297
• Main Authors: Yada, Shinichiro, Takamura, Noriaki, Inagaki-Ohara, Kyoko, O'Leary, Melissa K, Wasem, Christoph, Brunner, Thomas, Green, Douglas R, Lin, Tesu, Pinkoski, Michael J
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Apoptosis - genetics; Apoptosis - immunology; Atrophy; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow Transplantation - immunology; Bone Marrow Transplantation - pathology; Disease Models, Animal; Disease Progression; fas Receptor - biosynthesis; fas Receptor - physiology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - mortality; Graft vs Host Disease - pathology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Knockout; Radiation Chimera; Spleen - cytology; Spleen - immunology; Spleen - transplantation; Transplantation Conditioning; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.3.1291

Graft-vs-host disease (GVHD) is a devastating, frequently fatal, pathological condition associated with lesions in specific target organs, including the intestine, liver, lung, and skin, as well as pancytopenia and alopecia. Bone marrow (BM) atrophy is observed in acutely diseased animals, but the underlying mechanisms of hemopoietic stem cell depletion remained to be established. We used an experimental mouse model of acute GVHD in which parental cells were injected into F(1) hosts preconditioned by sublethal irradiation. The resulting graft-vs-host response was kinetically consistent, resulting in lethality within 3 wk. We observed disease pathology in the liver and small intestine, and consistent with previous observations, we found BM atrophy to be a factor in the onset of acute disease. The product of the protooncogene, p53, is known to be a key player in many physiological examples of apoptosis. We investigated the role of p53 in the apoptosis of BM cells (BMC) during the development of acute disease and found that at least one copy of the p53 gene is necessary for depletion of BM and subsequent lethality in host animals. BM depletion was preceded by induction of the death receptor, Fas, on the surface of host stem cells, and induction of Fas was coincidental with the sensitization of BMC to Fas-mediated apoptosis. Our data indicate that BM depletion in acute GVHD is mediated by p53-dependent up-regulation of Fas on BMC, which leads to Fas-dependent depletion and subsequent disease.