Prevention of Fas-mediated hepatic failure by transferrin

Lesnikov, Vladimir; Lesnikova, Marina; Shulman, Howard M.; Wilson, Heather M.; Hockenbery, David M.; Köcher, Markus; Pierpaoli, Walter; Deeg, H. Joachim

doi:10.1038/labinvest.3700035

Cited by 14 publications

(6 citation statements)

References 39 publications

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“…Following treatment, changes in liver iron content tended to occur rapidly (as early as 3-4 hours), as observed in previous studies [3,13,14]. Changes were most prominent after injection of JO2 ( baseline 280±121 vs 857± 134 μg/g dry liver after JO2; N=5, p< 0.01).…”

Section: Resultssupporting

confidence: 82%

“…JO2 antibody was administered via intraperitoneal injection at doses of 0.4 mg/g recipient body weight [13]. …”

Section: Methodsmentioning

confidence: 99%

“…Liver and sections of duodenum were prepared by standard techniques and analyzed to determine the presence of GVHD, cytotoxic changes, apoptosis and the presence of iron deposition [13,14] at different intervals after a given treatment.…”

Section: Methodsmentioning

confidence: 99%

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Disruption of Iron Regulation after Radiation and Donor Cell Infusion

Karoopongse

Marcondes

Yeung

et al. 2016

Biology of Blood and Marrow Transplantation

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Iron overload is common in patients undergoing hematopoietic cell transplantation (HCT). Peri-transplant events, such as total body irradiation (TBI) and the effects of donor cell infusion may contribute to iron overload, in addition to disease-associated anemia and red blood cell transfusions. Using murine models, we show complex time- and dose-dependent interactions of TBI and transplanted donor cells with expression patterns of iron regulatory genes in the liver. Infusion of allogeneic or syngeneic donor T lymphocytes increased serum iron, transiently up-regulated interleukin-6 (IL-6) and hepcidin (Hamp), and down-regulated ferroportin1 (Fpn1). After 7 to 14 days, however, changes were significant only with allogeneic cells. TBI (200-400 Gy) also induced IL-6 and Hamp expression but had little effect on Fpn1. TBI combined with allogeneic donor cell infusion resulted in modest early up-regulation of IL-6, followed by a decline in IL-6 levels and Hamp as well as Fpn1, and was accompanied by increased liver iron content. Injection of Fas-Ligand-deficient T lymphocytes from gld mice resulted in substantially lower alterations of gene expression than infusion of wild type T cells. The agonistic anti-Fas antibody, JO2, triggered early up-regulation of Stat3 and IL-6, followed by an increase in Hamp and decreased expression of Fpn1 by 7 to 14 days, implicating Fas as a key modulator of gene expression in HCT. Minimal histologic changes were observed in mouse liver and duodenum. These data show profound and interacting effects of TBI and cell transplantation on the expression of iron regulatory genes in murine recipients. Alterations are largely related to induction of cytokines and Fas-dependent signals.

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Section: Resultssupporting

confidence: 82%

“…JO2 antibody was administered via intraperitoneal injection at doses of 0.4 mg/g recipient body weight [13]. …”

Section: Methodsmentioning

confidence: 99%

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Disruption of Iron Regulation after Radiation and Donor Cell Infusion

Karoopongse

Marcondes

Yeung

et al. 2016

Biology of Blood and Marrow Transplantation

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“…Non-transformed murine and human hepatocyte cell lines, NMH (Balb/c-derived) and HH4, were developed by Jean Campbell, PhD [14,15]. …”

Section: Methodsmentioning

confidence: 99%

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

Karoopongse

et al. 2013

Biology of Blood and Marrow Transplantation

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Hepatic iron overload is common in patients undergoing hematopoietic cell transplantation. We showed previously in a murine model that transplantation of allogeneic T cells induced iron deposition and down-regulation of hepcidin (Hamp) in hepatocytes. We hypothesized that hepatic injury was related to disrupted iron homeostasis triggered by the interaction of Fas-ligand, expressed on activated T cells, with Fas on hepatocytes. In the current study, we determined the effects of modified expression of the Flice inhibitory protein (FLIP long [FLIPL]), which interferes with Fas signaling, on the impact of Fas-initiated signals on the expression of IL-6 and Stat3 and their down-stream target, Hamp. To exclude a possible contribution by other pathways, we used agonistic anti-Fas antibodies (rather than allogeneic T cells) to trigger Fas signaling. Inhibition of FLIPL by RNA interference resulted, as expected, in enhanced hepatocyte apoptosis in response to Fas signals, but also in decreased levels of IL-6, Stat3 and Hamp. In contrast, over-expression of FLIPL protected hepatocytes against agonistic anti-Fas antibody-mediated apoptosis, and increased the levels of IL-6 and Stat3, thereby maintaining the expression of Hamp in an NF-κB-dependent fashion. In vivo over-expression of FLIPL in the liver via hydrodynamic transfection, similarly, interfered with Fas-initiated apoptosis and prevented down-regulation of IL-6, Stat3 and Hamp. These data indicate that Fas-dependent signals alter the regulation of iron homeostasis and suggest that signals initiated by Fas may contribute to peri-transplant iron accumulation.

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“…Besides iron-related effects, there is evidence of cytoprotective effects of transferrin that are independent of iron binding. In murine in vivo models, pretreatment of mice with transferrin protected marrow cells against gammairradiation-induced cell death (Lesnikov et al, 2001) and prevented Fas-mediated hepatocyte death and liver failure (Lesnikov et al, 2004). The protective mechanism involved downregulation of several proapoptotic factors and upregulation of antiapoptotic signals.…”

Section: Discussionmentioning

confidence: 99%

Effect of repeated apotransferrin administrations on serum iron parameters in patients undergoing myeloablative conditioning and allogeneic stem cell transplantation

et al. 2006

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Summary Myeloablative conditioning prior to allogeneic stem cell transplantation causes a rapid increase in transferrin saturation and potentially toxic non‐transferrin‐bound iron (NTBI) in plasma. We have studied the ability of repeatedly administered apotransferrin to maintain this iron in a transferrin‐bound form. Twenty adult patients undergoing myeloablative conditioning and allogeneic stem cell transplantation were enrolled to receive apotransferrin with one of three dosage regimens. Ten consecutive patients with the same preconditioning were studied as controls. At the highest dose level, full transferrin saturation and appearance of NTBI were prevented in five of the eight patients. Serum iron increased significantly more in the patients receiving apotransferrin than in the controls and remained elevated until erythropoietic recovery. From the increment of iron saturation and the amount of endogenous and administered apotransferrin, an average 180 μmol of iron per day was bound to transferrin during the first 4 d after the start of the conditioning therapy. Thereafter, iron accumulation levelled off in most patients. The results suggested that about half of the amount of iron normally transported to erythropoiesis was initially released to plasma after induction of the erythroid arrest. Complete iron binding with apotransferrin would apparently require very high apotransferrin doses.

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Prevention of Fas-mediated hepatic failure by transferrin

Cited by 14 publications

References 39 publications

Disruption of Iron Regulation after Radiation and Donor Cell Infusion

Disruption of Iron Regulation after Radiation and Donor Cell Infusion

Allogeneic Transplantation, Fas Signaling, and Dysregulation of Hepcidin

Effect of repeated apotransferrin administrations on serum iron parameters in patients undergoing myeloablative conditioning and allogeneic stem cell transplantation

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