Hematopoietic Cell Transplantation and Iron Overload

造血细胞移植和铁过载

• 批准号: 8235938
• 负责人: H. JOACHIM DEEG
• 金额: $ 43.81万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235938
• 关键词: Abbreviations; Acute; Allogenic; Anemia; Apoptosis; Apoptotic; Appearance; Binding; Blood Circulation; Bone Marrow Diseases; CD95 Antigens; Cells; Cessation of life; Chronic; Clinical; Complication; Data; Deposition; Down-Regulation; Enterocytes; Erythrocyte Transfusion; Erythropoiesis; Event; Ferritin; Hepatic; Hepatocyte; Homeostasis; Homologous Transplantation; Infection; Inferior; Infusion procedures; Injury; Injury to Liver; Interleukin-6; Intervention; Intestinal Mucosa; Intestines; Iron; Iron Overload; Lead; Ligation; Liver; Mediating; Modeling; Mus; Organ; Outcome; Oxidation-Reduction; Parents; Patients; Pattern; Physiological; Proteins; Regulation; Regulator Genes; Reporting; Risk; Role; Secondary to; Signal Transduction; T-Lymphocyte; TNFRSF6 gene; TNFSF6 gene; Therapeutic Intervention; Tissue Grafts; Tissues; Toxic effect; Transferrin; Transplant Recipients; Transplantation; Transplantation Conditioning; Tumor Necrosis Factor Ligand Superfamily Member 6; Whole-Body Irradiation; Wild Type Mouse; absorption; conditioning; crosslink; cytokine; cytotoxic; graft vs host disease; hematopoietic cell transplantation; hepcidin; improved; insight; metal transporting protein 1; mortality; prevent; prophylactic; protective effect; public health relevance; receptor-mediated signaling; response; transferrin receptor 2

DESCRIPTION (provided by applicant): Iron overload is common in patients undergoing hematopoietic cell transplantation (HCT) and recent reports show increased non-relapse mortality in patients with iron overload as determined by increased levels of ferritin. Contributing pre-transplant causes include enhanced intestinal iron absorption secondary to anemia, and red blood cell transfusions. Peri- and post-transplant events appear to further enhance iron accumulation, which may contribute to the clinical picture of hepatic graft-versus-host disease (GVHD). Iron homeostasis is regulated by factors expressed primarily in liver and intestinal tract, both of which are targets of conditioning-related toxicity and of GVHD. Preliminary results in murine models indicate that transplantation of allogeneic (but not syngeneic) T lymphocytes results in altered expression of hepcidin and ferroportin 1, and dysregulation of iron homeostasis. Activated allogeneic T lymphocytes express Fas-ligand (CD178), which crosslinks Fas receptor (CD95), prominently expressed on hepatocytes, thereby inducing hepatic injury. We hypothesize that Fas-mediated signals, which induce apoptosis in hepatocytes, also interfere with the expression of hepcidin, thereby disrupting physiologic regulation of iron levels. However, iron loading also appears to modulate Fas signals, which would lead to two way interactions. Preliminary data suggest that exogenous transferrin (Tf) provides protection against iron accumulation, Fas-induced apoptosis and manifestations of GVHD in this setting by enhancing expression of anti-apoptotic proteins, possibly via transferrin receptor 2. We propose in Aim 1 to characterize the impact of transplantation of allogeneic T lymphocytes on iron homeostasis in murine models. Specifically, we will a) determine the pattern of dysregulation of iron homeostasis and the effect of total body irradiation (TBI), b) determine signals that lead to alterations of hepcidin expression, and c) determine interactions of Fas signals and iron regulation on apoptotic responses in hepatocytes. In Aim 2 we will characterize the impact of iron on the interaction of pro-apoptotic and cytoprotective signals in hepatocytes and develop strategies that would prevent hepatocyte injury in mice transplanted with allogeneic T lymphocytes. Specifically, we will a) characterize the effect of iron loading and ApoTf on transplant-related hepatic injury, and b) determine the effects of protective interventions other than Tf on hepatic injury and iron deposition. These studies will provide insights into the role of iron in hepatic injury in transplant recipients and should lead to improved strategies to prevent GVHD and improve transplant outcome. PUBLIC HEALTH RELEVANCE: New insights from these studies should lead to the identification of targets for prophylactic or therapeutic interventions aimed at preventing or reducing iron overload and toxicity, not only in the setting of transplantation, but also in other patients who suffer from iron overload and the associated acute and chronic complications.

描述（由申请人提供）：铁超负荷在接受造血细胞移植（HCT）的患者中很常见，最近的报告显示，铁超负荷患者的非复发死亡率增加，这取决于铁蛋白水平的增加。移植前的促成因素包括贫血继发的肠道铁吸收增强和红细胞输注。移植周围和移植后事件似乎进一步增强铁积累，这可能有助于肝移植物抗宿主病（GVHD）的临床表现。铁稳态受主要在肝脏和肠道中表达的因素调节，这两者都是调理相关毒性和 GVHD 的目标。小鼠模型的初步结果表明，同种异体（但不是同基因）T 淋巴细胞移植会导致铁调素和铁转运蛋白 1 表达的改变以及铁稳态的失调。激活的同种异体 T 淋巴细胞表达 Fas 配体 (CD178)，该配体与肝细胞上显着表达的 Fas 受体 (CD95) 交联，从而诱导肝损伤。我们假设 Fas 介导的信号会诱导肝细胞凋亡，也会干扰铁调素的表达，从而破坏铁水平的生理调节。然而，铁负荷似乎也会调节 Fas 信号，这将导致双向相互作用。初步数据表明，外源性转铁蛋白 (Tf) 可能通过转铁蛋白受体 2 增强抗凋亡蛋白的表达，从而针对铁积累、Fas 诱导的细胞凋亡和 GVHD 表现提供保护。我们在目标 1 中建议描述其影响同种异体 T 淋巴细胞移植对小鼠模型铁稳态的影响。具体来说，我们将 a) 确定铁稳态失调的模式和全身照射 (TBI) 的影响，b) 确定导致铁调素表达改变的信号，以及 c) 确定 Fas 信号和铁调节对细胞凋亡的相互作用肝细胞中的反应。在目标 2 中，我们将描述铁对肝细胞中促凋亡和细胞保护信号相互作用的影响，并制定预防移植同种异体 T 淋巴细胞的小鼠肝细胞损伤的策略。具体来说，我们将a）表征铁负荷和ApoTf对移植相关肝损伤的影响，b）确定Tf以外的保护性干预措施对肝损伤和铁沉积的影响。这些研究将深入了解铁在移植受者肝损伤中的作用，并应改进预防 GVHD 和改善移植结果的策略。 公共卫生相关性：这些研究的新见解应有助于确定预防或治疗干预的目标，旨在预防或减少铁超负荷和毒性，不仅在移植过程中，而且在其他患有铁超负荷和铁超负荷的患者中。相关的急性和慢性并发症。