IN UTERO TRANSPLANTATION IN BETA-THALASSEMIA

描述：β-地中海贫血是最常见的遗传性疾病之一。 在人类身上，并有越来越多的全球分布。目前的常规 这种使人衰弱的血红蛋白疾病的治疗方法复杂、昂贵， 而且不能治愈。造血干细胞移植可能 治愈了b地中海贫血，但与移植相关的发病率和死亡率 相当可观。此外，干细胞移植受到缺乏的限制。 合适的组织相容干细胞捐献者。胎儿检测的出现 现在提供了一个评估宫内治疗的机会 血红蛋白疾病以及免疫缺陷疾病和代谢疾病 疾病。子宫内移植有可能增加捐赠者 通过绕过与出生后相关的免疫屏障而形成的池 移植不匹配的细胞，也将允许治疗 在严重的病理性发作之前。据推测， 造血干细胞在子宫内的植入提供了一个永久的来源 在b-地中海贫血小鼠模型中的正常红细胞。在目标1中， B-地中海贫血的严重程度与植入率的关系 供体细胞的分化与血液学的矫正 宫内移植后小鼠b-地中海贫血的表现 被定义。在目标2中，免疫调节机制在控制中的作用 出生前后b-地中海贫血患者HSC植入和分化的研究 将对老鼠进行研究。在目标3中，促红细胞生成素在调节 子宫内移植的造血干细胞的植入和分化 调查过了。这项提案的目标是确定 造血干细胞在急性髓系白血病小鼠模型中的对照植入 B-地中海贫血和检查有潜力的移植程序 这种常见遗传性血液病在临床试验中的适用性 无序。

DESCRIPTION: Beta-thalassemia is one of the most common inherited disorders in man and has an increasingly global distribution. Current conventional therapies for this debilitating hemoglobinopathy are complicated, expensive, and are not curative. Hematopoietic stem cell (HSC) transplantation may cure b-thalassemia, but transplant-related morbidity and mortality is substantial. Additionally, stem cell transplantation is limited by the lack of suitable histocompatible stem cell donors. The advent of fetal testing now provides an opportunity to evaluate in utero therapy for hemoglobinopathies as well as immunodeficiency disorders and metabolic diseases. Transplantation in utero has the potential to increase the donor pool by circumventing the immunological barriers associated with post-natal transplantation of mismatched cells, and would also allow for treatment before the onset of serious pathological episodes. It is hypothesized that engraftment of hematopoietic stem cells in utero provides a permanent source of normal red blood cells in murine models of b-thalassemia. In aim 1, the relationships between the severity of b-thalassemia, engraftment and differentiation of donor cells and correction of the hematologic manifestations of murine b-thalassemia after in utero transplantation will be defined. In aim 2, the role of immune-mediated mechanisms in the control of HSC engraftment and differentiation in pre- and post-natal b-thalassemic mice will be studied. In aim 3, the role of erythropoietin in regulation of engraftment and differentiation of HSC transplanted in utero will be investigated. The goal of this proposal is to determine the mechanisms that control engraftment of hematopoietic stem cells in murine models of b-thalassemia and to examine transplant procedures that have potential applicability in clinical trials for this common heritable hematologic disorder.