TRANSLATIONAL STRATEGIES FOR PANCREATIC ISLET XENOTRANSPLANTATION IN NHP

NHP 胰岛异种移植的翻译策略

• 批准号: 8357464
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357464
• 关键词: Breeding; CD28 gene; Carbohydrates; Clinical; Family suidae; Funding; Future; Goals; Graft Survival; Grant; Immune response; Immunosuppressive Agents; Incidence; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Macaca; Macaca mulatta; Methods; National Center for Research Resources; Neonatal; Operating Rooms; Pathology; Pathway interactions; Primates; Principal Investigator; Reagent; Regimen; Research; Research Infrastructure; Resources; Services; Site; Source; Surface; TNFRSF5 gene; TNFSF5 gene; Tacrolimus; Testing; Therapeutic immunosuppression; Time; Tissues; Transplantation; United States National Institutes of Health; Xenograft procedure; base; cost; implantation; islet; novel; research study; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goals of this project are: 1) to investigate the survival and function of porcine islet xenographs in rhesus macaques using a novel Costimulation blockade-based regimen and 2) to prolong islet xenograph survival by optimizing new and existing stimulation blockade-based immunosuppressive therapies and testing new methods and sites of islet implantation. Using pancreatectomized macaque recipients, neonatal islets, and a Costimulation-blockade based regimen target the CD40L pathway, we have had excellent initial success with porcine islet transplantation; achieving long-term graft survival, function, and insulin independence. The clinical usefulness of anti-CD40L reagents was limited by significant incidence of thromboembolic complications. Building on these results we are looking at alternative immunosuppressive regiments targeting other Costimulation pathways such as CD40 and CD28. We have had encouraging but inconsistent results with these regimens. Some cases provided excellent xenograft survival. Current and future directions will focus on more clinically applicable reagents such as Tacrolimus and LFA-31g. Islets from pigs bred to lack the surface carbohydrate Gal on all tissues (Gal-KO) may circumvent the robust innate immune response that is usually mounted against transplanted xenogeneic tissues. Initial results investigating the transplantation of Gal-KO islets under cover of Costimulation blockade-based regimens have been extremely good and are ongoing. Each experiment employs significant Yerkes resources, including veterinary staff, Rhesus macaques, operating room time and staff, and pathology services.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的目标是：1）使用基于共刺激阻断的新方案研究恒河猴中猪胰岛异种移植物的存活和功能，2）通过优化新的和现有的基于刺激阻断的免疫抑制疗法并测试胰岛植入的新方法和部位来延长胰岛异种移植物的存活。使用胰腺切除的猕猴受体、新生胰岛和靶向CD 40 L通路的基于共刺激-阻断的方案，我们在猪胰岛移植方面取得了极好的初步成功;实现了长期移植物存活、功能和胰岛素依赖性。抗CD 40 L试剂的临床应用受到血栓栓塞并发症显著发生率的限制。基于这些结果，我们正在寻找针对其他共刺激途径（如CD 40和CD 28）的替代免疫抑制方案。这些方案取得了令人鼓舞但不一致的结果。一些病例提供了极好的异种移植物存活。目前和未来的方向将集中在更临床适用的试剂，如他克莫司和LFA-31 g。来自所有组织上缺乏表面碳水化合物Gal的猪的胰岛（Gal-KO）可以规避通常针对移植的异种组织的强烈的先天免疫应答。在基于共刺激阻断的方案的掩护下，研究Gal-KO胰岛移植的初步结果非常好，并且正在进行中。每个实验都使用了大量的耶基斯资源，包括兽医人员、恒河猴、手术室时间和工作人员以及病理学服务。