Immunomodulatory and regenerative effects of mesenchymal stem cells on allografts

间充质干细胞对同种异体移植物的免疫调节和再生作用

• 批准号: 8706764
• 负责人: NORMA S. KENYON
• 金额: $ 223.67万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706764
• 关键词: Acceleration; Acute; Address; Allogenic; Allografting; Amelia; Autologous; Award; Biological Markers; Biopsy; Bone Marrow Aspiration; Cell model; Chicago; Chronic; Clinical; Clinical Trials; Collaborations; Collection; Complex; Coupled; Data; Data Analyses; Diabetes Mellitus; Doctor of Philosophy; Dose; Engraftment; Experimental Designs; Gene Proteins; Genomics; Goals; Histocompatibility; Histocompatibility Testing; Hyperglycemia; Illinois; Immunity; Immunologics; Immunosuppression; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous infusion procedures; Islets of Langerhans Transplantation; Joints; Kidney; Kidney Transplantation; Lead; Liver; Macaca fascicularis; Magnetic Resonance Imaging; Maintenance; Marrow; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metabolic; Metabolic Control; Methods; Modeling; Monitor; Monkeys; Mus; Organ; Organ Donor; Organ Transplantation; Outcome; Paper; Predictive Value; Process; Property; Proteomics; Protocols documentation; Publications; Publishing; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Research; Research Institute; Research Personnel; Role; Sampling; Site; Solid; Source; Stem cell transplant; Supercomputing; Testing; Time; Tissues; Transplantation; United States National Institutes of Health; Universities; Waiting Lists; Work; allograft rejection; base; data mining; design; experience; graft function; improved; in vivo; intrahepatic; intravenous administration; islet; islet allograft; kidney allograft; liver biopsy; lymph nodes; macrophage; meetings; migration; monocyte; nonhuman primate; peripheral blood; programs; prospective; regenerative; repaired; research study; response; skin allograft; success; tool; transplantation typing

DESCRIPTION (provided by applicant): Our goal is to identify a safe and optimally effective mesenchymal stem cell (MSC)-based co-transplant protocol that can be tested in the clinical setting to improve long-term islet and renal allograft survival and function. We will utilize cynomolgus monkey models of cellular (Project 1) and solid organ (Project 2) allotransplantation, in conjunction with genomics and proteomics to define MSC product release criteria and potential biomarkers (Core B), as well as sophisticated tools for data analysis (Core C), to undertake the following. Aim 1: Utilize an intrahepatic islet/ MSC co-transplant model to identify the optimal source of the MSC product, i.e. recipient or third party, by determining how MSC origin impacts islet allograft outcome and to assess the efficacy of third party activated MSC (aMSC) in allogeneic renal transplantation. Aim 2. Determine if intravenous administration of the optimal MSC product can reproducibly lead to reversal of islet allograft rejection and subsequent maintenance of or improvement in islet function and to define the effect of aMSC third party MSC on ischemia reperfusion injury. Aim 3. Analyze the proteomic, genomic and phenotypic changes that occur in the peripheral blood and tissues of monkey recipients of islet or renal/MSC co-transplants to define biomarkers common to MSC efficacy/non-efficacy for both models, as well as markers unique to each transplant type. Aim 4. Undertake transplants with the optimal MSC source, coupled with prospective monitoring of potential biomarkers, in order to enable pilot clinical trials of islet or renal/MSC co-transplantation. These aims will be addressed in a coordinated effort with 2 Projects supported by 3 Cores: Project 1: Mesenchymal stem cell enhancement of islet engraftment and long term survival, University of Miami, PI: Norma S. Kenyon, PhD and Project 2: Mesenchymal stem cell enhancement of organ allograft repair and long term survival, University of Illinois at Chicago, PI: Amelia Bartholomew, MD. The three supporting cores will be: Core A: Administrative Core, University of Miami, PI: Norma S. Kenyon, PhD; Core B: Genomics and Proteomics Core, Scripps Research Institute, La Jolla, PI: Daniel Salomon, MD; and Core C: Supercomputing and Multidimensional Data Analysis Core, University of Illinois at Urbana-Champaign, PI: Peter Bajcsy, PhD. This team will provide a powerful mechanism for data mining and analysis, thereby resulting in acceleration of the discovery process, as compared to the outcome of a single PI working to put together genomic and proteomic data in the context of complex clinical, immunologic and metabolic outcomes. RELEVANCE: At present, the potential benefit of the clinical administration of MSC on vascularized and non-vascularized allografts is not known. Upon completion of the proposed studies we hope to develop uniform MSC product release criteria based on discrete and reproducible genomic and proteomic markers. We will know if activation of MSC overcomes variability among donors related to MHC type and immunomodulatory/regenerative properties, thereby enhancing the potential for uniform efficacy in vivo. Project Leader: KENYON, N Project 1: Mesenchymal Stem Cell Enhancement of Islet Engraftment and Long-Term Survival (Description as provided by applicant): We have observed significant enhancement of islet engraftment, prolongation of islet allograft survival and reversal of rejection in cynomolgus monkey recipients of intrahepatic islet/MSC cotransplants. Our goal is to identify a safe and optimally effective transplant protocol that can be tested in the clinical setting to improve long-term islet allograft survival and function. MSC are being utilized experimentally and clinically to mediate inflammation and immunity in a variety of settings; however, the impact of MSC MHC in relation to the recipient and to the cellular or solid organ donor on transplant outcomes has not been defined. In the setting of islet allotransplantation, MHC matching is not taken into consideration when pairing a donor with a recipient. As MSC expansion and banking can take up to 6 weeks, it would be impractical in the clinical setting to utilize MSC from the islet donor. The alternatives are recipient MSC, which would require bone marrow aspiration and MSC expansion/banking while the recipient is on the waiting list, or MSC from a third party. The effect of MHC on islet/MSC transplant outcomes will be studied in Aim 1: To utilize a cynomolgus monkey, intrahepatic islet/MSC co-transplant model to identify the optimal source of the MSC product, i.e., recipient or third-party, by determining how MSC origin impacts islet allograft outcome. Our preliminary data suggests that IV administration of additional MSC at the time of islet allograft destabilization allows for reversal of rejection and, ultimately, enhancement of graft function. This will be assessed in Aim 2: To determine if intravenous administration of the optimal MSC product can reproducibly lead to reversal of islet allograft rejection and subsequent maintenance of or improvement in islet function. Based on published data regarding the mechanisms responsible for the immunomodulatory effect of MSC, as well as on our own preliminary data (Projects 1 and 2), we hypothesize that transplantation of MSC into the liver with islets, as well as infusion of IV MSC post-transplant will result in the induction of T regulatory cells, recruitment of regulatory monocytes/macrophages and endothelial precursors to sites of inflammation (i.e., the graft site) and migration of MSC to lymph nodes draining the graft site. We will undertake studies to address this in Aim 3: To define predictive biomarkers of MSC efficacy and non-efficacy in renal and islet allograft responses. Finally, the data from Projects 1 and 2 and Cores B and C will be incorporated in Aim 4: To undertake transplants with the optimal MSC source, dose and timing of administration, coupled with prospective monitoring of potential biomarkers, in order to enable a pilot clinical trial of islet/MSC cotransplantation. RELEVANCE: Islet cell transplantation reverses hyperglycemia and normalizes metabolic control. However, broader application to the cure of type 1 diabetes has been limited by the requirement for chronic immunosuppression and the scarcity of organ donors. MSC delivery with the islets may limit inflammation, enhance islet revascularization and reduce the number of donors needed to achieve insulin independence. Furthermore, MSC administration may constitute a safe and effective way to reverse rejection episodes.

描述（由申请人提供）：我们的目标是确定一种安全且最有效的基于间充质干细胞（MSC）的联合移植方案，该方案可以在临床环境中进行测试，以改善胰岛和肾脏移植的长期存活和功能。我们将利用食蟹猴细胞（项目1）和实体器官（项目2）同种异体移植模型，结合基因组学和蛋白质组学来定义MSC产品释放标准和潜在的生物标志物（核心B），以及复杂的数据分析工具（核心C），开展以下工作。目的1：利用肝内胰岛/间充质干细胞共移植模型，通过确定MSC来源如何影响胰岛同种异体移植结果，并评估第三方激活的MSC （aMSC）在同种异体肾移植中的疗效，来确定MSC产品的最佳来源，即受体或第三方。目标2。确定静脉注射最佳间充质干细胞产品是否可重复性地逆转胰岛异体移植排斥反应并随后维持或改善胰岛功能，并确定aMSC第三方间充质干细胞对缺血再灌注损伤的影响。目标3。分析猴子接受胰岛或肾脏/间充质干细胞联合移植的外周血和组织中发生的蛋白质组学、基因组学和表型变化，以确定两种模型中MSC有效性/非有效性的共同生物标志物，以及每种移植类型的独特标志物。目标4。采用最佳的MSC来源进行移植，同时对潜在的生物标志物进行前瞻性监测，以便进行胰岛或肾脏/MSC联合移植的试点临床试验。这些目标将通过3个核心支持的2个项目的协调努力来解决：项目1：胰岛移植的间充质干细胞增强和长期生存，迈阿密大学，PI: Norma S. Kenyon博士；项目2：器官移植修复的间充质干细胞增强和长期生存，伊利诺伊大学芝加哥分校，PI: Amelia Bartholomew医学博士。三个支持核心将是：核心a：行政核心，迈阿密大学，PI；诺玛·凯尼恩博士；核心B：基因组学和蛋白质组学核心，Scripps研究所，La Jolla, PI: Daniel Salomon， MD；Core C：超级计算和多维数据分析核心，伊利诺伊大学厄巴纳-香槟分校，PI: Peter Bajcsy博士。该团队将为数据挖掘和分析提供强大的机制，从而加速发现过程，而不是单个PI在复杂的临床，免疫学和代谢结果的背景下将基因组和蛋白质组学数据放在一起。