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: 8318050
• 负责人: NORMA S. KENYON
• 金额: $ 273.4万
• 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/8318050
• 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）：我们的目标是确定可以在临床环境中测试的安全且最佳有效的间充质干细胞（MSC）的共同移植方案，以改善长期胰岛和肾脏同种异体移植的生存和功能。我们将利用细胞（项目1）和固体器官（项目2）同种异体移植以及基因组学和蛋白质组学的结合来定义MSC产品释放标准和潜在的生物标志物（Core B），以及以下数据分析（CORE C），以进行以下内容。目标1：通过确定MSC来源如何影响同种异体移植结果，利用肝内胰岛/ MSC共同移植模型来识别MSC产品的最佳来源，即接受者或第三方。 AIM 2。确定最佳MSC产品的静脉内给药是否可以重复导致胰岛移植排斥的逆转以及随后维持胰岛功能或改善的胰岛功能，并确定AMSC第三方MSC对缺血再灌注损伤的影响。 AIM 3。分析在猴子或肾脏/MSC共同移植物的外周血和组织中发生的蛋白质组学，基因组和表型变化，以定义MSC效率/非效率的生物标志物，用于两种模型，以及每种移植类型所独有的标记。 AIM 4。使用最佳MSC来源进行移植，再加上对潜在生物标志物的前瞻性监测，以实现胰岛或肾脏/MSC共转移的试验临床试验。 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.三个支持核心将是：核心A：迈阿密大学的行政核心：PI：Norma S. Kenyon博士；核心B：基因组学和蛋白质组学核心，Scripps研究所，La Jolla，PI：医学博士Daniel Salomon；和Core C：超级计算和多维数据分析核心，伊利诺伊大学PI Urbana-Champaign大学：Peter Bajcsy，PhD。与单个PI在复杂的临床，免疫，免疫学和代谢结果的背景下，该团队将提供有力的数据挖掘和分析机制，从而导致发现过程的加速。 相关性：目前，尚不清楚MSC临床给药对血管化和非血管化同种异体移植的潜在益处。拟议的研究完成后，我们希望基于离散和可重复的基因组和蛋白质组学标记制定统一的MSC产品释放标准。我们将知道MSC的激活是否克服了与MHC类型和免疫调节/再生特性相关的供体之间的可变性，从而增强了体内均匀疗效的潜力。 项目负责人：Kenyon，N 项目1：间充质干细胞增强胰岛植入和长期生存 （申请人提供的描述）：我们观察到胰岛植入的显着增强，同种异体移植生存的延长以及cynomolgus Monkey的拒绝症的逆转，肝脏内胰岛/MSC共移植植物的受体。我们的目标是确定可以在临床环境中测试的安全且最佳有效的移植方案，以改善长期胰岛同种异体移植的生存和功能。 MSC在实验和临床上被用于介导各种环境中的炎症和免疫力。但是，尚未定义MSC MHC对受体以及细胞或固体器官供体对移植预后的影响。在胰岛同种异体移植的情况下，将MHC匹配在将捐赠者与A配对时不考虑 接受者。由于MSC扩展和银行业务最多可能需要6周，因此在临床上是不切实际的 设置从胰岛供体中利用MSC。替代方案是接收者MSC，在接收者处于候补名单上或第三方的MSC时，需要骨髓吸引力和MSC扩展/银行业务。 MHC对胰岛/MSC移植结果的影响将在AIM 1中进行研究：通过确定MSC Origins Hights Emplots Impacts Impacts Implations Implations Impacts Implots Implations Impacts iSlet iSlet Alrograft promotion，使用MSC产品的最佳来源，即使用MSC产品的最佳来源，以识别MSC产品的最佳来源。我们的初步数据表明，在胰岛同种异体移植不稳定时，静脉注射额外的MSC可以逆转排斥反应，并最终增强了移植功能。这将在AIM 2中进行评估：确定最佳MSC产品的静脉内给药是否可以可重复地导致胰岛同种异体移植排斥的逆转，并随后维持胰岛功能或改善胰岛功能。基于有关负责MSC免疫调节作用的机制以及我们自己的初步数据的公开数据（项目1和2），我们假设将MSC移植到肝脏中，胰岛和输注后IV MSC的植入术会导致themitials/thansplant的诱导，招募多个培训概念，招募众多概述，招募众多的概述，招募众多的概述，到炎症部位（即移植部位）和MSC迁移到淋巴结淋巴结，排出移植部位。我们将在AIM 3中进行研究，以解决肾脏和胰岛同种异体移植反应中MSC功效和非效率的预测生物标志物。最后，项目1和2和核心B和C的数据将被纳入AIM 4：用最佳的MSC源，给药的剂量和时间安排进行移植，再加上潜在生物标志物的前瞻性监测，以实现胰岛/MSC共移植的试验临床试验。 相关性：胰岛细胞移植会逆转高血糖并将代谢控制归一化。但是，对1型糖尿病的治疗的更广泛应用受到慢性免疫抑制和器官捐献者稀缺的要求的限制。使用胰岛输送的MSC可能会限制炎症，增强胰岛血运重建并减少实现胰岛素独立性所需的供体数量。此外，MSC给药可能构成一种逆向拒绝发作的安全有效方法。