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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目的目标是：1）使用一种新型的基于COTAIMATION BLOCKADE BOCKADE的方案和2）研究猪猕猴在猕猴中的生存和功能，以及2）2）通过优化基于新的和现有的基于基于刺激性的免疫抑制作用的治疗疗法，并测试Islet Implet的新方法和位点，以延长胰岛主体的生存。使用胰腺切除的猕猴，新生儿胰岛和基于结构性阻滞的方案CD40L途径，我们在猪胰岛移植方面取得了巨大的初始成功。实现长期的移植物生存，功能和胰岛素独立性。抗CD40L试剂的临床有用性受到血栓栓塞并发症的重大发生率的限制。在这些结果的基础上，我们正在研究针对其他共刺激途径（例如CD40和CD28）的替代免疫抑制团。这些方案的结果令人鼓舞但不一致。某些情况提供了出色的异种移植生存。当前和未来的方向将集中于更临床适用的试剂，例如他克莫司和LFA-31G。饲养猪的胰岛缺乏所有组织上的表面碳水化合物GAL（gal-ko）可能会规避通常安装在移植的异种组织上的强大先天免疫反应。调查基于CORTIMUTUCTION封锁方案的Gal-KO小岛移植的初步结果非常好，并且正在进行中。每个实验都采用大量的Yerkes资源，包括兽医，恒河猴，手术室时间和人员以及病理学服务。