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

项目总结(见说明)： 骨髓间充质干细胞(MSC)在动物模型中表现出免疫抑制和再生特性。虽然人类在移植物抗宿主病、自身免疫性疾病和肌肉骨骼再生方面的临床试验已经启动，但在移植方面的应用仍然滞后。小鼠和临床前实验模型提出了对同种异体致敏、MSC表型和功能特征的重复性以及移植后最佳适应症的具体关注。 在该计划的这个项目2中，将进行疗效研究，以确定优化MSC的免疫抑制和再生功能。在目标1中，我们将测试与未激活的MSC相比，干扰素激活的MSC在形态和功能上是否具有更大的同质性，我们将在亚治疗免疫抑制方案的设置下，确定MHC相合的MSC与不相合的MSC对移植肾功能的相对贡献。我们将在目标2和目标3中测试MSC在减少延长冷缺血时间造成的组织损伤方面的有效性，通过与核心B和C的合作，包括免疫反应、组织活检和内皮祖细胞频率的纵向评估的次要结果指标将与主要结果指标100天无排斥反应生存相关，以确定疗效。评估将通过核心B进行蛋白质和基因组分析，然后在核心C使用经典统计学和一种新的机器学习方法进行汇编和统计分析，这种方法有可能从小样本中最大限度地进行数据分析。这些疗效研究将在临床前肾移植模型中进行，并在项目1中的临床前胰岛模型中平行进行。行政核心将促进该项目、项目1与核心B和C之间的协同作用，该核心将协调每月电话会议，跟踪样本到核心，并跟踪时间表和交付成果的进展。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.