Hematopoietic Cell Transplantation and Iron Overload

造血细胞移植和铁过载

基本信息

批准号：
7888104
负责人：
H. JOACHIM DEEG
金额：
$ 46.15万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
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/7888104
关键词：
Abbreviations Acute Allogenic Anemia Apoptosis Apoptotic Appearance Binding Blood Circulation Bone Marrow Diseases CD95 Antigens Cell Transplantation Cells Cessation of life Chronic Clinical Complication Data Deposition Down-Regulation Enterocytes Erythrocyte Transfusion Erythropoiesis Event Ferritin Hematopoietic 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 Relapse 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 hepcidin improved insight metal transporting protein 1 mortality prevent prophylactic protective effect public health relevance receptor-mediated signaling response transferrin receptor 2

项目摘要

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）：在接受造血细胞移植（HCT）的患者中，铁超负荷很常见，最近的报告显示，铁超负荷患者的非释放死亡率增加，这取决于铁蛋白水平升高。造成移植前的原因包括贫血继发的肠道吸收和红细胞输血。移植事件和移植后事件似乎进一步增强了铁的积累，这可能有助于肝移植物抗抗宿主病（GVHD）的临床情况。铁稳态受主要在肝脏和肠道中表达的因素调节，这两者都是与调节有关的毒性和GVHD的靶标。鼠模型的初步结果表明，同种异体（但不是合成性）T淋巴细胞的移植会导致肝素和铁蛋白素1的表达改变，而铁稳态的失调。激活的同种异体T淋巴细胞表达FAS-配体（CD178），它交叉链接FAS受体（CD95）在肝细胞上显着表达，从而诱导肝损伤。我们假设FAS介导的信号诱导肝细胞凋亡，也干扰了肝素的表达，从而破坏了铁水平的生理调节。但是，铁负载似乎也调节FAS信号，这将导致两种相互作用。初步数据表明，在这种情况下，外源性转铁蛋白（TF）通过增强抗凋亡蛋白的表达，可能通过转铁蛋白受体2（可能是通过转铁蛋白受体2。在鼠模型中铁稳态上同种异体T淋巴细胞移植。具体而言，我们将a）确定铁稳态失调的模式和全身照射的影响（TBI），b）确定信号，导致肝素表达改变，c）确定FAS信号和铁调节对凋亡的相互作用肝细胞的反应。在AIM 2中，我们将表征铁对肝细胞中促凋亡和细胞保护信号相互作用的影响，并制定策略，以防止用同种异体T淋巴细胞移植的小鼠中肝细胞损伤。具体而言，我们将a）表征铁负荷和APOTF对移植相关肝损伤的影响，b）确定除TF以外的保护性干预措施对肝损伤和铁沉积的影响。这些研究将提供有关铁在移植受者中肝损伤中的作用的见解，并应提高预防GVHD并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导致识别旨在防止或减少铁超负荷和毒性的预防或治疗干预措施的靶标，不仅在移植的情况下，而且在其他患有铁超负荷和铁超负荷和遭受的患者中相关的急性和慢性并发症。