TRANSLATIONAL STRATEGIES FOR PANCREATIC ISLET XENOTRANSPLANTATION IN NHP

NHP 胰岛异种移植的翻译策略

• 批准号: 8172418
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172418
• 关键词: Attention; Breeding; CD28 gene; Carbohydrates; Clinical; Computer Retrieval of Information on Scientific Projects Database; Family suidae; Funding; Future; Goals; Graft Survival; Grant; Immune response; Immunosuppressive Agents; Incidence; Institution; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Macaca; Macaca mulatta; Methods; Neonatal; Operating Rooms; Pathology; Pathway interactions; Reagent; Regimen; Research; Research Personnel; 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; implantation; islet; islet xenograft; novel; research study; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this project are 1) to investigate the survival and function of porcine islet xenografts in rhesus macaques using a novel costimulation blockade-based regimen 2) to prolong islet xenograft survival by optimizing new and existing costimulation 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 targeting the CD40L pathway, our lab had excellent initial success with porcine islet transplantation, achieving long-term graft survival, function, and insulin independence. However, the clinical usefulness of anti-CD40L reagents was limited by significant incidence of thromboembolic complications. Building on these results, we have turned our attention to alternative immunosuppressive regimens targeting other costimulation pathways such as CD40 and CD28. We have had encouraging, though somewhat inconsistent, results with these regimens, which in some cases provided excellent xenograft survival. Current and future directions will focus on more clinically applicable reagents such as Tacrolimus and LFA-3Ig. 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; these experiments are ongoing. Each experiment employs significant Yerkes resources including veterinary staff, rhesus monkeys, operating room time and staff, and pathology services.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的目标是1）使用一种新型的基于cotimulation封锁的治疗方案来研究恒河猴猕猴中猪胰岛异种移植物的生存和功能2），以优化基于新的和现有的基于基于COLLADADE BLOCKADE BLOCKADE BLOCKADE BLOCKADE BLOCKADE BLOCKADE BLOCKADE BLOCKAFTADE的免疫疗法和测试新方法和新方法和iSlet Implet的位置，以延长胰岛的异种移植生存。 使用胰腺切除猕猴的受体，新生儿胰岛以及针对CD40L途径的基于结构性阻滞的方案，我们的实验室在猪胰岛移植，实现长期移植生存，功能，功能，功能和胰岛素独立性方面取得了良好的初始成功。然而，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，我们将注意力转向了针对其他共刺激途径（例如CD40和CD28）的替代免疫抑制方案。 我们对这些方案的结果令人鼓舞，尽管有些不一致，但在某些情况下，这些方案提供了极好的异种移植生存。 当前和未来的方向将集中于诸如他克莫司和LFA-3ig等临床上适用的试剂。 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。 研究基于封锁的治疗方案覆盖的Gal-Ko胰岛移植的初步结果非常好。这些实验正在进行中。 每个实验都采用重要的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。