Disruption of Iron Regulation after Radiation and Donor Cell Infusion

Abstract

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.

Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation

“…In an autologous HSCT mice model, iron overload was detected to be associated with increased melphalan and busulfan toxicities through a pharmacodynamic interaction [ 24 ]. In a recent study, the interacting effects of total body irradiation and cell transplantation on the expression of iron regulatory genes had contributed to iron overload in murine recipients [ 25 ].…”