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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的目标是：1）使用一种新的基于共刺激阻断的方案研究猪胰岛异种移植物在恒河猴中的存活和功能; 2）通过优化新的和现有的基于共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，我们的实验室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。然而，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。 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（如CD 40和CD 28）的替代免疫抑制方案。 我们已经取得了令人鼓舞的结果，尽管有些不一致，这些方案在某些情况下提供了极好的异种移植物存活率。 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-3 Ig。 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已经非常好;这些实验正在进行中。 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。