TRANSPLANTATION OF UMBILICAL CORD BLOOD PROGENITOR CELLS

试图降低与此相关的发病率和死亡率 同种异体骨髓移植，亚洲的临床研究人员， 澳大利亚、欧洲、北美和南美都对脐带进行了评估 脐带血和胎盘血作为造血干细胞的替代来源 用于移植的祖细胞。 1988年10月至9月 1994年，51名年龄1.3-47.8岁的恶性肿瘤患者（n=30） 非恶性 (n=21) 疾病接受同种异体脐带血治疗 清髓治疗后的造血救援。脐带血 移植物是从新生儿兄弟姐妹捐赠者那里收集的（n = 45, 35 HLA 相同） 和 10 个 HLA-在 1-3 个位点不匹配）和不相关的供体（n=6；1 个 HLA- 102 个基因座相同且 5 个 HLA 不匹配）。临床经验 日期表明脐带血确实含有长期骨髓 重新增殖细胞并且数量足以在大多数情况下植入 体重低于 40 公斤的受赠者。然而，时间到 造血恢复延迟。中性粒细胞和中性粒细胞的中位时间 对于未接受治疗的患者，血小板恢复时间分别为 28.5 天和 48 天。 移植后用造血生长因子治疗。而且， 46 名可评估患者中，有 11 名患者的供体来源的造血功能不存在或不完整 患者。该提案的总体目标是制定战略 优化原始造血细胞和定向造血细胞的数量 脐带血接种并确定离体效果 祖细胞扩增对供体来源造血恢复的影响 同种异体脐带血的接受者。在具体目标 1 中，我们 提议描述长期文化的功能能力 脐带血中的起始细胞。我们将确定 这些原始细胞的增殖能力和多谱系潜力 与成人骨骼中发现的对应物直接比较的祖细胞 骨髓和成人外周血。在具体目标 2 中，我们将确定 扩大原始数量和数量的最佳培养条件 脐带血中的定型祖细胞以及发育 逆转录病毒转导的最佳程序。并且，在具体目标 3 中，我们 将进行同种异体脐带血的序贯临床试验 成人和儿童接受者的移植，首先使用未经修饰的 随后体外扩增脐带血接种物。在一起， 这些实验的结果将使我们能够确定 脐带血与成人骨的异同 骨髓和外周血祖细胞以及优化 用于临床移植的造血祖细胞 大小收件人。

In an attempt to reduce the morbidity and mortality associated with allogeneic bone marrow transplantation, clinical investigators in Asia, Australia, Europe, north America and South America have evaluated umbilical cord and placental blood as an alternate source of hematopoietic stem and progenitor cells for transplantation. Between October 1988 and September 1994, 51 patients aged 1.3-47.8 years with malignant (n=30) and nonmalignant (n=21) disorders received allogeneic umbilical cord blood for hematopoietic rescue after myeloablative therapy. Umbilical cord blood grafts were collected from neonatal sibling donors (n=45, 35 HLA-identical and 10 HLA-mismatched at 1-3 loci) and unrelated donors (n=6; 1 HLA- identical and 5 HLA-mismatched at 102 loci). The clinical experience to date demonstrates that umbilical cord blood does contain long-term marrow repopulating cells and in numbers sufficient for engraftment in most recipients weighing les than 40 kilograms. However, the time to hematopoietic recovery is delayed. The median time to neutrophil and platelet recovery is 28.5 and 48 days, respectively, in patients not treated with hematopoietic growth factors after transplantation. Moreover, donor-derived hematopoiesis was absent or incomplete in 11 of 46 evaluable patients. The overall aim of this proposal is to develop strategies for optimizing the number of primitive and committed hematopoietic cells in the umbilical cord blood inoculum and determine the effect of ex vivo progenitor cell expansion on donor-derived hematopoietic recovery in recipients of allogeneic umbilical cord blood. In Specific Aim 1, we propose to characterize the functional capacities of the long-term culture initiating cells in umbilical cord blood. We will determine the proliferative capacity and multilineage potential of these primitive progenitors with direct comparisons to counterparts found in adult bone marrow and adult peripheral blood. In Specific Aim 2, we will determine the optimal culture conditions for expanding the number of primitive and committed progenitor cells in umbilical cord blood as well as develop the optimal procedure for retroviral transduction. And, in Specific Aim 3, we will perform sequential clinical trials of allogeneic umbilical cord blood transplantation in adult and pediatric recipients, first using unmodified and subsequently ex vivo expanded umbilical cord blood inocula. Together, the results of these experiments will allow us to determine the similarities and differences between umbilical cord blood, adult bone marrow and peripheral blood progenitors as well as optimize the number of hematopoietic progenitors cells for use in clinical transplantation in all size recipients.