TRANSPLANTATION OF UMBILICAL CORD BLOOD PROGENITOR CELLS

脐带血祖细胞移植

• 批准号: 6103009
• 负责人: JOHN M WAGNER
• 金额: $ 20.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-06 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103009
• 关键词: blood disorder; blood treatment; bone marrow; cell growth regulation; cell sorting; cell transplantation; clinical trials; cryopreservation; genetic transduction; hematopoietic stem cells; homologous transplantation; human subject; human therapy evaluation; interleukin 2; natural killer cells; tissue /cell culture; transplant rejection; umbilical cord

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.

为了降低与糖尿病相关的发病率和死亡率， 异基因骨髓移植，亚洲的临床研究者， 澳大利亚、欧洲、北美和南美已对脐带缆进行了评估 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1998年9月 1994年，51例年龄为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， 清髓性治疗后的造血挽救。脐带血 移植物收集自新生儿同胞供体（n = 45，35个HLA相同的 和10个HLA-1 - 3位点不匹配的供体）和无关供体（n = 6; 1个HLA-1位点不匹配的供体）。 在102个基因座处相同和5个HLA错配）。临床经验， 一项新的研究表明，脐带血中确实含有长期骨髓 在大多数情况下， 体重低于40公斤的收件人。然而，时间 造血恢复延迟。中性粒细胞和 血小板恢复分别为28.5天和48天， 移植后用造血生长因子治疗。此外，委员会认为， 在46例可评价的患者中，11例患者的供者源性造血功能缺失或不完全。 患者本提案的总体目标是制定战略， 优化原始和定型造血细胞的数量， 脐带血接种物，并确定离体效果 祖细胞扩增对供体来源的造血恢复的影响 接受异基因脐带血的人。在具体目标1中， 建议描述长期培养的功能能力 脐带血中的原始细胞。康贝特人将以 这些原始细胞的增殖能力和多系潜能 与成人骨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 扩大原核细胞数量的最佳培养条件， 脐带血中的定向祖细胞，以及开发 逆转录病毒转导的最佳方法。在第三个具体目标中，我们 将进行异基因脐带血的连续临床试验 在成人和儿童接受者中进行移植，首先使用未经修饰的 随后离体扩增脐带血接种物。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的数量， 造血祖细胞用于临床移植 大小收件人。