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，已在动物模型中显示出免疫抑制和再生特性。尽管在移植物抗宿主病、自身免疫性疾病和肌肉骨骼再生方面已经开始了人体临床试验，但在移植方面的应用却落后于人。小鼠和临床前实验模型引起了特别的关注 同种异体致敏性、MSC表型和功能表征的再现性以及移植后的最佳适应症在该项目2中，将进行功效研究以确定MSC的最佳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，并且我们将确定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关贡献。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在减少来自长时间冷缺血的组织损伤中的功效，次要结果测量包括免疫应答、组织学和免疫学的纵向评估。 活组织检查和内皮祖细胞频率将与主要结果测量，100天无排斥生存率相关，以确定疗效。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中使用经典生物学和新型机器学习方法进行编译和统计学分析，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， 这是为了证明MSC在使基线免疫抑制最小化方面的功效或非功效。

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.