Cord Blood Graft Engineering to Improve Engraftment and Reduce GVHD

脐带血移植工程可改善移植并减少 GVHD

• 批准号: 10478151
• 负责人: Elizabeth J Shpall
• 金额: $ 53.24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478151
• 关键词: Acute; Acute Graft Versus Host Disease; Award; Blood; Blood Cells; Blood Platelets; Bone Marrow; CD44 gene; CSF3 gene; Cell Therapy; Cell surface; Cells; Clinical Trials; Coculture Techniques; Collaborations; Cytotoxic T-Lymphocytes; Data; Disease model; Dose; E-Selectin; Engineering; Engraftment; Enzymes; Failure; Fucosyltransferase; Funding; Goals; Guanosine Diphosphate Fucose; Hematopoietic; Hematopoietic stem cells; Homing; Human; Immunity; Inflammation; Inflammatory; L-Selectin; Ligands; Liver; Logistics; Marrow; Mediating; Morbidity - disease rate; Morphology; Natural Killer Cells; Outcome; Patients; Peripheral Blood Stem Cell; Phenotype; Physiological; Pre-Clinical Model; Procedures; Recovery; Refractory; Regenerative Medicine; Reporting; Research Design; Series; Shapes; Site; Steroids; Stress; Supplementation; System; Testing; Therapeutic Uses; Time; Tissues; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Virus; Work; base; galactoside 3-fucosyltransferase; gastrointestinal; graft vs host disease; improved; mesenchymal stromal cell; migration; mortality; mouse model; neutrophil; next generation; novel; peripheral blood; reconstitution; small molecule; stem cells; sugar; tumor

PROJECT SUMMARY Cord blood transplantation (CBT) has clear advantages over transplantation with bone marrow or peripheral blood stem cells, but its wider use has been limited by the low dose of stem and progenitor cells in CB units, leading to delays in engraftment and a substantial rate of engraftment failure. During the past PO1 funding period, we developed a marrow-derived mesenchymal stromal cell (MSC)-CB coculture system that allowed us to significantly accelerate the time to neutrophil and platelet engraftment. This advance was paralleled by results showing that ex vivo cell-surface fucosylation of CB, using the fucosyltransferase (FT)-6 enzyme with GDP-fucose can boost engraftment by promoting CB homing to marrow. Thus, in Project 1, we now propose a revised series of studies directed to our long-term goal: bringing the results of CBT in line with outcomes being reported for G-CSF-mobilized peripheral blood progenitor cells (Aims 1 and 2). This effort will test CBT based on the combination of MSC-expansion of CB cells followed by exofucosylation with FT-7 a second fucosyltransferase that is more physiologic than FT-6 and could be even more effective at enhancing engraftment in the marrow. Additionally, graft-versus-host disease (GVHD) continues to restrict the utility of CBT, an issue we did not address specifically during the past PO1 award. Rates of grade III-IV GVHD after CBT range from 5% to 30%. In our patients, those with acute liver and gastrointestinal (GI) GVHD have significantly benefited from MSC treatment. In a xenogenic GVHD model, we have observed that fucosylated MSCs can enhance homing to sites of inflammation, resulting in a striking survival benefit compared with the outcome of unmanipulated MSC treatment. We have also recently observed that CB tissue-derived MSCs are logistically easier to obtain and expand much more rapidly than marrow-derived MSCs. Thus we now propose to test whether CB tissue-derived, fucosylated MSCs can be used to abrogate acute, steroid-refractory liver and/or GI GVHD (Aim 3). The interactive potential of this project is considerable, for example, the clinical trial in Aim 1 will likely stimulate collaborations with Project 2 (reconstitution of virus-specific CTLs), Project 3 (NK cell recovery) and Project 4 (recovery of tumor-specific immunity). Finally, we would stress that many of the findings from Project 1 will not be restricted to CBT, but could extend well beyond times to engraftment to settings as diverse as GVHD and regenerative medicine.

项目概要 脐带血移植（CBT）与骨髓或骨髓移植相比具有明显的优势 外周血干细胞，但其广泛应用受到干细胞剂量低和 CB 单位中的祖细胞，导致植入延迟和显着的植入率 失败。在过去的 PO1 资助期间，我们开发了一种骨髓源性间充质基质 细胞 (MSC)-CB 共培养系统使我们能够显着加快中性粒细胞和 血小板植入。这一进展与表明离体细胞表面 CB 的岩藻糖基化，使用岩藻糖基转移酶 (FT)-6 酶与 GDP-岩藻糖可以增强 通过促进CB归巢到骨髓来进行植入。因此，在项目 1 中，我们现在提出修订后的 针对我们长期目标的一系列研究：使 CBT 的结果与结果保持一致 据报道，G-CSF 动员的外周血祖细胞（目标 1 和 2）。这项努力将 基于 CB 细胞的 MSC 扩增和外岩藻糖基化相结合来测试 CBT FT-7 是第二种岩藻糖基转移酶，比 FT-6 更具生理性，甚至可能更 有效增强骨髓植入。 此外，移植物抗宿主病 (GVHD) 继续限制 CBT 的使用，这是我们研究的一个问题 过去PO1颁奖期间没有具体提及。 CBT 后 III-IV 级 GVHD 发生率 范围从 5% 到 30%。在我们的患者中，患有急性肝脏和胃肠道 (GI) GVHD 的患者患有 MSC 治疗显着受益。在异种 GVHD 模型中，我们观察到 岩藻糖基化 MSC 可以增强对炎症部位的归巢，从而实现惊人的存活率 与未经操作的 MSC 治疗的结果相比有益处。我们最近也有 观察到 CB 组织来源的 MSC 在逻辑上更容易获得并扩展得更多 比骨髓来源的 MSC 更快。因此，我们现在建议测试 CB 组织是否源自， 岩藻糖基化 MSC 可用于消除急性、类固醇难治性肝脏和/或胃肠道 GVHD（目标 3）。 这个项目的互动潜力是相当大的，比如Aim 1的临床试验将 可能会刺激与项目 2（病毒特异性 CTL 的重建）、项目 3（NK 细胞恢复）和项目4（肿瘤特异性免疫的恢复）。最后我们要强调的是 项目 1 的许多发现不仅限于 CBT，还可以远远超出 CBT 范围。 植入到 GVHD 和再生医学等不同环境中的时间。