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

Abstract

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.

Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice

“…We had shown previously that Fas-initiated hepatocyte injury was attenuated or prevented by apotransferrin. 13,16 Since alloactivated T lymphocytes express Fas ligand, and Fas signaling is involved in GVHD, 17,18 we postulated that pretreatment of NOD/SCID mice with apotransferrin before histoincompatible T-cell infusion would interfere with hepatic injury and liver iron deposition. Results illustrated in Figure 1C through F support this hypothesis by showing substantial reduction in hepatocyte apoptosis and serum transaminase elevations.…”

Regulation of apoptosis during homeostasis and disease in the intestinal epithelium

“…The presence of TNF‐α or interferon‐γ can upregulate Fas to increase cell sensitivity to FasL, resulting in caspase‐8 activation and apoptosis 39. Fas activation has been described as an important regulator of the pathogenesis of UC and graft‐versus‐host disease 38,40,41. Other p53 targets besides death domain‐containing receptor activation may be involved in this process because TNFR1 knockout mice are still susceptible to radiation‐induced p53‐dependent apoptosis 32…”

Atypical Acute Graft-Versus-Host Disease

“…5 Recently, the death receptor, Fas of the target cell induced by p53, was reported to play an important role in the mechanism of acute GVHD. 6 In addition, soluble Fas ligand has been shown to reduce murine acute GVHD. 7 In our case, Fas was expressed on the lesional follicular epithelium and peripheral epidermis (data not shown).…”