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The Role of p53 and Fas in a Model of Acute Murine Graft-versus-Host Disease¹

Shinichiro Yada^*,, Noriaki Takamura^*, Kyoko Inagaki-Ohara^*, Melissa K. O’Leary, Christoph Wasem, Thomas Brunner, Douglas R. Green, Tesu Lin^* and Michael J. Pinkoski^2,,¶

^* Division of Gastroenterology, Department of Medicine, Northwestern Medical School, Chicago IL 60611; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Immunopathology, Institute for Pathology, University of Bern, Bern, Switzerland; Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and ^¶ Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

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 F₁ 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.