Hematopoietic Progenitor Cells

描述（由申请人提供）：脐带血（CB）用于骨髓移植缺乏兄弟姐妹或非亲属供体的患者恢复造血功能。CB的一个主要缺点是低细胞剂量导致中性粒细胞植入延迟和植入失败率高。本研究的主要假设是，在移植前体外扩增的CB祖细胞比未处理的CB祖细胞提供更快的中性粒细胞植入和更少的植入失败。有两种细胞群被认为与髓细胞的快速恢复有关：1)成熟祖细胞和2)原始造血干细胞。在这笔拨款中，我们将进行三个连续的II期临床试验，以评估体外扩展的CB移植物产生成熟祖细胞或原始干细胞。第一项试验是先前R01的延续，将评估CD34+前体选择性扩增的CB移植物。第二项试验将评估CB移植物，其中更原始的CB细胞扩增，使用早期作用的生长因子和赠款中描述的新技术。基于这些研究的结果，第三个试验将随机分配患者接受未处理的CB祖细胞和扩展的CB祖细胞，使用前两个试验中的扩展方法，导致最快的植入。我们预计感染性并发症将是这些试验中发病率和死亡率的主要原因。虽然扩大的CB可能会加速中性粒细胞的植入并减少移植后早期的感染，但它可能不会影响与延迟免疫恢复相关的感染。经常报道CB受体的免疫重建延迟。本基金提出的CB纯化和扩增方法可能会导致淋巴样细胞的选择性损失，从而进一步损害免疫重建。因此，我们计划全面评估纳入拟议试验的CB受体的免疫重建。一般免疫功能和巨细胞病毒特异性免疫重建将被研究，因为有多种可用的、互补的检测方法和将执行这些检测的共同研究者的专业知识。通过在第三项试验中随机分配患者，我们将能够估计未操作与扩展的CB受体中CB扩展技术的相对疗效以及免疫重建。

DESCRIPTION (provided by applicant): Umbilical cord blood (CB) is used to restore hematopoiesis in bone marrow transplant patients lacking sibling or unrelated donors. A major disadvantage of CB is the low cell dose with resultant delays in neutrophil engraftment and a high rate of engraftment failure. The major hypothesis of this grant is that CB progenitors expanded ex vivo prior to transplantation will provide more rapid neutrophil engraftment and less engraftment failure than unmanipulated CB. There are two populations that have been proposed to be responsible for rapid myeloid recovery: 1) mature progenitor cells, and 2) primitive hematopoietic stem cells. In this grant we will conduct three sequential phase II clinical trials to evaluate CB grafts expanded ex vivo to generate mature progenitors or primitive stem cells. The first trial, a continuation of the previous R01, will evaluate CB grafts in which committed CD34+ precursors have been selectively expanded. The second trial will evaluate CB grafts in which more primitive CB cells are expanded, using earlier-acting growth factors and novel technology described in the grant. Based upon the findings of these studies, the third trial will randomize patients to receive CB progenitors which are unmanipulated vs. expanded, using the expansion methodology in the first two trials that results in the fastest engraftment. We anticipate that infectious complications will be a major cause of morbidity and mortality in these trials. Although expanded CB may hasten neutrophil engraftment and reduce infections early posttransplant, it may not affect infections associated with delayed immune recovery. Delays in immune reconstitution in CB recipients are frequently reported. It is possible that the CB purification and expansion methods proposed in this grant, which result in selective loss of lymphoid cells, could further compromise immune reconstitution. Thus, we plan to comprehensively evaluate the immune reconstitution of CB recipients enrolled on the proposed trials. General immune function and CMV-specific immune reconstitution will be studied, because of the multiple, complimentary assays available and the expertise of the co-investigators who will be performing them. By randomizing patients in the third trial, we will be able to make an estimate of the relative efficacy of CB expansion technology as well as immune reconstitution in recipients of unmanipulated vs. expanded CB.