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的特性。虽然人类临床试验已经在移植物抗宿主病、自身免疫性疾病和肌肉骨骼再生方面启动，但在移植方面的应用仍然滞后。小鼠和临床前实验模型引起了特别的关注 在本计划的这个项目2中，将进行疗效研究，以确定MSC的最佳免疫抑制和再生功能，以确定同种异体致敏作用、MSC表型和功能特征的重复性以及移植后的最佳适应症。在目标1中，我们将测试与非激活的MSC相比，干扰素激活的MSC在形态和功能上是否提供更大的同质性，我们将确定在亚治疗免疫抑制方案的设置下，MHC相合的MSC与不相合的MHC对移植肾功能的重新贡献。我们将在目标2和目标3中，通过与核心B和C的合作，测试MSC在减少长期冷缺血损伤组织方面的有效性，次要结果测量包括对免疫反应、组织的纵向评估 活检和内皮祖细胞频率将与主要结局指标--100天无排斥反应生存期--相关联，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，这种方法有可能最大限度地从小样本中进行数据分析。 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， 这是为了证明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 regenerafive properties in animal models. While human clinical trials have been initiated in graft versus host disease, autoimmune disorders, and musculoskeletal regenerafion, applicationto 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 funcfions 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 relafive contribufion of MHC matched MSC to mismatched ones on renal allograft function in the setting of a sub-therapeufic immunosuppressive regimen. We will test the efficacy of MSC in reducing tissue injury from prolonged cold ischemia fimes in Aim 2 and in Aim 3, through the collaborafion 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 rejecfion free survival, to define efficacy. Assessments will be undertaken proteomically and genomically via Core B and then compiled and stafisfically analyzed in Core C using both classical statisfics 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.