Mesenchymal stem cell enhancement of islet engraftment and long term survival

间充质干细胞增强胰岛移植和长期存活

• 批准号: 8514492
• 负责人: NORMA S. KENYON
• 金额: $ 51.82万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8514492
• 关键词: Address; Allogenic; Allografting; Biological Markers; Bone Marrow Aspiration; Chronic; Clinical; Clinical Trials; Coupled; Data; Dendritic Cells; Dose; Engraftment; Event; Goals; Human; Hyperglycemia; Immunity; Immunosuppression; Inflammation; Inflammatory; Instruction; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous infusion procedures; Islets of Langerhans Transplantation; Lead; Liver; Macaca fascicularis; Maintenance; Marrow; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metabolic Control; Modeling; Monitor; Organ Donor; Outcome; Protocols documentation; Publishing; Regulatory T-Lymphocyte; Rodent; Site; Solid; Source; T cell regulation; Testing; Time; Transplantation; Waiting Lists; allograft rejection; base; graft function; improved; intrahepatic; intravenous administration; islet; islet allograft; kidney allograft; lymph nodes; macrophage; migration; monocyte; nonhuman primate; precursor cell; programs; prospective; regenerative; response

PROJECT SUMMARY (See instructions); 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 3rd 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.

项目摘要（请参阅说明）； 我们已经观察到胰岛植入的显着增强，同种异体移植存活率的延长以及肝脏内胰岛/MSC共移植抑制剂的cynomolgus猴子受体中排斥的逆转。我们的目标是确定可以在临床环境中进行测试以改进的安全且最佳有效的移植协议 长期同种异体移植生存和功能。 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，因此在临床环境中使用胰岛供体的MSC是不切实际的。替代方案是接收者MSC，在收件人在等候名单上，需要骨髓式吸引力和MSC扩展/银行业，或第三次从第三名中使用MSC 派对。 MHC对胰岛/MSC移植结果的影响将在AIM 1中进行研究：要利用Cynomolgus Monkey，Haphepatic Islet/MSC Co-Transplant模型来确定MSC产品的最佳来源，即接受者或第三方，通过确定MSC Origin tagement tagement of MSC Origins implets iSlet islet iSlet同种异体属性。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的公开数据，以及 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节点排出移植部位。我们将进行研究 在目标3中解决了这一点：定义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的数据将纳入AIM 4：以最佳的MSC来源，剂量和给药时间进行移植，再加上对潜在生物标志物的前瞻性监测，以启用Islet/MSC Cotransplantation的PILOT临床试验。