Hematopoietic Cell Transplantation and Iron Overload

描述（由申请人提供）：铁超载在接受造血细胞移植（HCT）的患者中很常见，最近的报道显示，铁蛋白水平升高决定了铁超载患者的非复发死亡率增加。移植前的原因包括继发于贫血的肠道铁吸收增强和红细胞输注。移植前后的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宿主病（GVHD）的临床表现。铁稳态是由主要在肝脏和肠道表达的因子调节的，两者都是调节相关毒性和GVHD的靶点。小鼠模型的初步结果表明，同种异体（而非同基因）T淋巴细胞移植导致hepcidin和铁转运蛋白1的表达改变，铁稳态失调。活化的同种异体T淋巴细胞表达Fas配体（CD178），其交联Fas受体（CD95），在肝细胞上显著表达，从而诱导肝损伤。我们假设fas介导的信号在诱导肝细胞凋亡的同时也干扰了hepcidin的表达，从而破坏了铁水平的生理调节。然而，铁负载似乎也会调节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）通过增强抗凋亡蛋白的表达，可能通过转铁蛋白受体2，对铁积累、fas诱导的细胞凋亡和GVHD的表现提供保护。我们在目的1中提出表征同种异体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hepcidin表达改变的信号，以及c)确定Fas信号和铁调节在肝细胞凋亡反应中的相互作用。在Aim 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，并制定策略，防止同种异体T淋巴细胞移植小鼠的肝细胞损伤。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。这些研究将提供铁在移植受者肝损伤中的作用，并将导致改进预防GVHD和改善移植结果的策略。

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.