TRANSLATIONAL STRATEGIES FOR PANCREATIC ISLET XENOTRANSPLANTATION IN NHP

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目标是1)使用一种新的基于共刺激阻断的方案来研究恒河猴异种胰岛移植的存活和功能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和测试新的方法和胰岛植入的部位来延长异种胰岛移植的存活时间。 利用胰腺切除猕猴受体、新生胰岛，以及针对CD40L途径的共刺激-阻断方案，我们的实验室在猪胰岛移植方面取得了良好的初步成功，实现了移植物的长期存活、功能和胰岛素依赖。然而，抗CD40L试剂的临床应用受到血栓栓塞症并发症发生率的限制。在这些结果的基础上，我们将注意力转向针对其他共刺激途径的替代免疫抑制方案，如CD40和CD28。我们已经获得了令人鼓舞的结果，虽然有些不一致，但这些方案在某些情况下提供了极好的异种移植存活率。目前和未来的方向将集中在更多的临床适用的试剂，如他克莫司和LFA-3Ig。 培育成缺乏所有组织表面碳水化合物Gal的猪胰岛(Gal-KO)可能绕过通常针对移植的异种组织而建立的强大的先天免疫反应。在共刺激阻断方案的掩护下，对Gal-KO胰岛移植的初步调查结果非常好；这些实验正在进行中。 每个实验都使用了大量的耶克斯资源，包括兽医人员、恒河猴、手术室时间和人员以及病理服务。

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.