Hematopoietic Progenitor Cells

描述(申请人提供)：脐带血(CB)用于无兄弟姐妹或无血缘关系的骨髓移植患者恢复造血。CB的一个主要缺点是细胞剂量低，导致中性粒细胞植入延迟，植入失败率高。这项资助的主要假设是，移植前体外扩增的脐带血祖细胞将提供比未经处理的脐带血更快的中性粒细胞植入和更少的植入失败。有两个群体被认为是导致髓系快速恢复的原因：1)成熟的祖细胞，2)原始的造血干细胞。在这笔赠款中，我们将进行三项连续的II期临床试验，以评估体外扩增的CB移植物能否产生成熟的祖细胞或原始干细胞。第一个试验是先前R01的延续，将评估承诺的CD34前体被选择性扩展的CB移植物。第二个试验将使用更早起作用的生长因子和赠款中描述的新技术来评估脐带血移植，其中更原始的脐带血细胞被扩增。根据这些研究的结果，第三个试验将随机让患者接受未经操纵和扩大的脐带血祖细胞，使用前两个试验中的扩大方法学，导致最快的植入。我们预计，在这些试验中，感染性并发症将是导致发病率和死亡率的主要原因。尽管扩张的CB可以加速中性粒细胞的植入，减少移植后早期的感染，但它可能不会影响与免疫恢复延迟相关的感染。CB受者的免疫重建延迟是经常被报道的。这项资助中提出的CB纯化和扩增方法可能会进一步损害免疫重建，这些方法会导致淋巴细胞的选择性丢失。因此，我们计划全面评估参加拟议试验的脐带血受者的免疫重建情况。将研究一般免疫功能和CMV特异性免疫重建，因为有多种免费的分析方法可用，以及将执行这些分析的合作研究人员的专业知识。通过对第三个试验中的患者进行随机分组，我们将能够评估脐带血扩张技术的相对疗效，以及未经操作的脐带血与扩张的脐带血的受者的免疫重建。

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.