title: Disruption of Iron Regulation after Radiation and Donor Cell Infusion.
abstract: Iron overload is common in patients undergoing hematopoietic cell transplantation (HCT). Peritransplant 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 RBC 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 to 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ekapun
authors.initials: E
authors.lastname: Karoopongse
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: A Mario
authors.initials: AM
authors.lastname: Marcondes
authors.affiliation: Department of Anatomic Pathology, University of Washington, Seattle, Washington.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Yeung
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Holman
authors.affiliation: Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: Icogenex Bioincubator R&D, OncoSec Medical, Seattle, Washington.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington. Electronic address: jdeeg@fhcrc.org.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology*; D035925:Iron-Regulatory Proteins / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D013601:T-Lymphocytes / Q000378:metabolism; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation / Q000009:adverse effects*; D019014:fas Receptor / Q000502:physiology
chemical_list: D016207:Cytokines; D035925:Iron-Regulatory Proteins; D019014:fas Receptor; D007501:Iron
keywords: Donor cell infusion; Fas; Gene expression; Hepcidin; IL-6; Radiation