Mesenchymal stem cell enhancement of organ allograft repair and long term surviva

项目总结（见说明）： 间充质干细胞（MSC），从骨髓抽吸物扩增，已在动物模型中表现出免疫抑制和再生特性。虽然人类临床试验已经开始在移植物抗宿主病，自身免疫性疾病，和肌肉骨骼再生，移植的应用已经落后。小鼠和临床前实验模型已经引起了对同种异体致敏、MSC表型和功能表征的再现性以及移植后的最佳适应症的具体关注。 在该计划的项目2中，将进行疗效研究，以确定MSC的免疫抑制和再生功能。在目标1中，我们将测试当与非活化MSC相比时，干扰素γ活化MSC是否在形式和功能上提供更大的同质性，并且我们将定义在亚治疗免疫抑制方案的设置中，MHC匹配MSC与不匹配MSC对肾同种异体移植物功能的相对贡献。我们将通过与Cores B和C的合作，在目标2和目标3中测试MSC在减少长时间冷缺血引起的组织损伤方面的功效，次要结局指标包括免疫应答、组织活检和内皮祖细胞频率的纵向评估，将与主要结局指标100天无排斥存活率相关，以确定功效。将通过核心B进行蛋白质组学和基因组学评估，然后在核心C中使用经典统计学和新型机器学习方法进行汇编和统计学分析，该方法有可能最大限度地利用小样本量进行数据分析。这些疗效研究将在临床前肾移植模型中进行，以平行于项目1中临床前胰岛模型中的类似研究。管理核心将促进本项目、项目1以及核心B和C之间的协同作用，管理核心将协调每月电话会议，跟踪样本到核心，并跟踪时间表和可交付成果的进度。这些研究支持我们的长期目标，即证明MSC在最小化基线免疫抑制方面的有效性或无效性。

PROJECT SUMMARY (See Instructions): Mesenchymal stem cells (MSC), expanded from bone marrow aspirates, have demonstrated immunosuppressive and regenerative properties in animal models. While human clinical trials have been initiated in graft versus host disease, autoimmune disorders, and musculoskeletal regeneration, application to transplants has lagged behind. Murine and pre-clinical experimental models have raised specific concerns of allo-sensitization, reproducibility of MSC phenotypic and functional characterization, and optimal indication post-transplant. In this Project 2 of the Program, efficacy studies will be undertaken to define optimize immunosuppressive and regenerative functions of MSC. In aim 1, we will test whether interferon gamma activated MSC provide greater homogeneity in form and function when compared to non-activated MSC and we will define the relative contribution of MHC matched MSC to mismatched ones on renal allograft function in the setting of a sub-therapeutic immunosuppressive regimen. We will test the efficacy of MSC in reducing tissue injury from prolonged cold ischemia times in Aim 2 and in Aim 3, through the collaboration with Cores B and C, the secondary outcome measures which include longitudinal assessments of immune responses, tissue biopsies, and endothelial progenitor frequencies will be correlated to the primary outcome measure, 100-day rejection free survival, to define efficacy. Assessments will be undertaken proteomically and genomically via Core B and then compiled and statistically analyzed in Core C using both classical statistics and a novel machine learning approach which has the potential to maximize data analysis from small sample sizes. These efficacy studies will be undertaken in a pre-clinical renal transplant model to parallel similar studies in a pre-clinical islet model in Project 1. Synergy between this project, Project 1, and Cores B and C will be facilitated by the Administrative Core, which will coordinate monthly conference calls, track samples to the Cores, and follow the progress on timelines and deliverables. These studies support our long-term goal, which is to demonstrate MSC efficacy or non-efficacy in minimizing baseline immunosuppression.