Stem Cell Transplantation: Basic/Clinical Research

描述(由申请人提供)： 我们建议继续基础和临床研究的综合计划，以改善通过造血细胞移植(HCT)治疗获得性和遗传性非恶性血液疾病和骨髓增生异常综合征的患者。这两个临床项目追求异基因红细胞移植的两个共同总体目标。一是减少与条件调节相关的毒性和移植相关的并发症，包括移植物排斥反应和移植物抗宿主病(GVHD)。另一项是通过移植人类白细胞抗原半相合的骨髓细胞和无血缘关系的脐带血，扩大人类白细胞抗原配型相合和无关个体以外的造血细胞捐献者的选择范围。这两个临床前项目将使用一种有着成功转化为临床试验的长期历史的犬类模型。其中一个项目寻求进一步改进主要组织相容性复合体半相合HCT，部分通过探索生物和药物免疫抑制剂的组合，部分通过探索新的移植后化疗策略，结合开发的耐药基因转移方法。另一个项目建议进一步优化基因转移到造血细胞的有效性和安全性，测试基因转移在临床相关犬遗传性血液疾病中的疗效和安全性，并研究基因转移的长期后果。这四个研究项目得到了四个核心单位的支持，这些单位提供研究设计、数据处理、统计分析、方案管理、多中心试验的协调、移植后免疫功能评估、慢性移植物抗宿主病的管理和长期随访。从这笔赠款下的研究中得出的原则已经并将继续对骨髓和血液干细胞移植以及其他恶性和非恶性血液疾病患者的基因治疗产生广泛的影响。

DESCRIPTION (provided by applicant): We propose to continue an integrated program of basic and clinical research to improve treatment of patients with acquired and inherited nonmalignant blood disorders and myelodysplastic syndromes by hematopoietic cell transplantation (HCT). The two clinical projects pursue two shared overall objectives for allogeneic HCT. One is to reduce conditioning-related toxicities and transplantation associated complications including graft rejection and graft-versus-host disease (GVHD). The other is to broaden the choice of hematopoietic cell donors beyond HLA-matched related and unrelated individuals by including grafts of HLA-haploidentical marrow cells and unrelated cord blood. The two preclinical projects will use a canine model with a long history of successful translation into clinical trials. One Project seeks to further improve major histocompatibility complex haploidentical HCT, in part by exploring combinations of biological and pharmacological immunosuppressive agents and in part by exploring novel post-transplantation chemotherapy strategies in combination with methods of transfer of drug resistance genes developed The other Project proposes to further optimize efficacy and safety of gene transfer into hematopoietic cells, test the therapeutic efficacy and safety of gene transfer in a clinically relevant canine inherited blood disorder, and study long-term consequences of gene transfer. The four research projects are supported by four core units, which provide study design, data processing, statistical analyses, protocol management, and coordination of multi-center trials, assessment of immune functions after transplantation, management of chronic GVHD,and long-term follow-up. The principles derived from the studies under this grant have had and will continue to have broad implications for marrow and blood stem cell transplantation and gene therapy in the treatment of patients with other malignant and nonmalignant blood disorders.