TRANSPLANTATION OF UMBILICAL CORD BLOOD PROGENITOR CELLS

为了降低与以下疾病相关的发病率和死亡率 异基因骨髓移植，亚洲的临床研究人员， 澳大利亚、欧洲、北美和南美对脐带血进行了评估 脐带血和胎盘血作为造血干细胞和 用于移植的祖细胞。1988年10月至9月 1994年，51例年龄1.3-47.8岁的恶性肿瘤患者(n=30)和 21例接受异基因脐带血治疗的非恶性疾病 清髓治疗后的造血挽救。脐带血 移植物取自新生儿兄弟姐妹供者(n=45，35个人类白细胞抗原相合 10例1-3位点不相合的供者)和无血缘关系的供者(n=6； 102个位点完全相同，5个不相合)。临床经验与体会 数据显示，脐带血中确实含有长期骨髓 重新填充细胞，数量足以在大多数情况下植入 体重在40公斤以下的获奖者。然而，现在是时候 造血功能恢复延迟。中性粒细胞和中性粒细胞的中位时间 未治疗的患者血小板恢复时间分别为28.5天和48天 移植后应用造血生长因子治疗。此外， 46例可评估患者中有11例供者来源的造血功能缺失或不完全 病人。这项提议的总体目标是制定战略， 优化骨髓原始和定向造血细胞的数量 脐带血接种及体外效果的测定 造血祖细胞扩增对供者造血恢复的影响 异基因脐带血的接受者。在具体目标1中，我们 建议对长期文化的功能能力进行表征 脐带血中的启动细胞。我们将确定 这些原始细胞的增殖能力和多系潜能 与成人骨骼中发现的祖先直接比较的祖细胞 骨髓和成人外周血。在具体目标2中，我们将确定 扩大原始体和原始体数量的最适培养条件 脐带血中的定向祖细胞以及发育成 逆转录病毒转导的最佳程序。在具体目标3中，我们 将对异基因脐带血进行序贯临床试验 成人和儿童受者的移植，首先使用未经修改的 随后进行体外扩增脐血接种。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，以及优化数量 用于急性淋巴细胞白血病临床移植的造血祖细胞 确定收件人的大小。

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.