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: 10247041
• 负责人: Elizabeth J Shpall
• 金额: $ 53.2万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247041
• 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; 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.

项目摘要 脐带血移植（CBT）比用骨髓或 外周血干细胞，但其更广泛的用途受到低剂量的茎和 CB单元中的祖细胞，导致植入和植入率很高 失败。在过去的PO1资金期间，我们开发了一个骨髓来源的间充质基质 细胞（MSC）-CB共培养系统，使我们能够显着加速中性粒细胞的时间 血小板植入。结果表明，该进步与体内细胞表面相似 使用GDP-观糖的岩藻糖基转移酶（FT）-6酶可以增强CB 通过将CB归居摩根来植入。因此，在项目1中，我们现在提出了一项修订 针对我们的长期目标的一系列研究：将CBT的结果与结果保持一致 报道了G-CSF-Mobilized外周血祖细胞细胞（目标1和2）。这项努力会 基于CB细胞的MSC-膨胀的结合，然后与外生糖基化一起测试CBT FT-7第二个岩藻糖基转移酶比FT-6更生理，并且可能更多 有效增强骨髓中的植入。 此外，移植物抗宿主病（GVHD）继续限制CBT的效用，这是我们的问题 在过去的PO1奖中没有专门针对。 CBT之后的III-IV级GVHD率 从5％到30％不等。在我们的患者中，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 岩藻糖基化的MSC可以增强对炎症部位的归巢，从而产生惊人的存活率 与未经操纵的MSC治疗的结果相比。我们最近也有 观察到CB组织衍生的MSC在逻辑上更容易获得和扩展更多 比骨髓衍生的MSC迅速。因此，我们现在建议测试CB组织是否衍生的 葡萄糖基化的MSC可用于消除急性，类固醇难治性肝和/或GI GVHD（AIM 3）。 该项目的互动潜力很大，例如，AIM 1中的临床试验将 可能刺激与项目2（病毒特异性CTL的重构）的合作，项目3（NK 细胞恢复）和项目4（肿瘤特异性免疫的恢复）。最后，我们强调 项目1的许多发现将不限于CBT，但可能会远远超出 植入到GVHD和再生医学等各种环境的时间。