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，最近的报告显示，铁超载患者的无复发死亡率增加，这是由铁蛋白水平增加所决定的。移植前的原因包括继发于贫血的肠道铁吸收增强，以及红细胞输注。移植前后的事件似乎进一步增强了铁的积累，这可能有助于肝脏移植物抗宿主病(GVHD)的临床图景。铁稳态由主要在肝脏和肠道表达的因子调节，这两个因子都是条件性毒性和移植物抗宿主病的靶标。在小鼠模型中的初步结果表明，异基因(但不是同基因)T淋巴细胞移植会导致海普西丁和铁蛋白1的表达改变，并导致铁稳态的失调。活化的同种异体T淋巴细胞表达Fas配体(CD178)，它与肝细胞表面的Fas受体(CD95)发生交联性反应，从而导致肝损伤。我们假设，诱导肝细胞凋亡的Fas介导的信号也干扰了海普西丁的表达，从而扰乱了铁水平的生理调节。然而，铁负荷似乎也调制了Fas信号，这将导致双向相互作用。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，可能是通过转铁蛋白受体2，对铁蓄积、Fas诱导的细胞凋亡和GVHD的表现起到保护作用。在目标1中，我们建议表征同种异体T淋巴细胞移植对小鼠模型铁稳态的影响。具体地说，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Hepsidin表达变化的信号，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。在目标2中，我们将描述铁对肝细胞中促凋亡信号和细胞保护信号相互作用的影响，并开发预防同种异体T淋巴细胞移植小鼠肝细胞损伤的策略。具体地说，我们将a)表征铁负荷和载脂蛋白Tf对移植相关肝损伤的影响，以及b)确定除转铁蛋白以外的保护性干预措施对肝损伤和铁沉积的影响。这些研究将对铁在移植受者肝脏损伤中的作用提供见解，并应导致改进预防GVHD和改善移植结果的策略。 与公共卫生相关：这些研究的新见解应有助于确定预防或治疗干预的目标，以预防或减少铁超载和毒性，不仅在移植环境中，而且在其他铁超载及其相关急性和慢性并发症的患者中也是如此。

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.