Islet Core

核心摘要本U19建议旨在实现在已故患者情况下的胰岛移植耐受 (项目1)和活体(项目2)供体移植。这两个项目都依赖于使用单个 食蟹猴供胰岛在移植耐受研究中的应用。此外，用于研究的胰岛处理 项目2特别具有挑战性，因为它需要来自部分地区的足够数量和质量的胰岛。 切除胰腺以恢复血糖控制。这种集中式小岛隔离的主要服务目标是质量 U19的控制和移植核心设施将成为高质量猴子的可靠资源 项目1和2中的胰岛移植所需的胰岛，允许一致的实验结果。我们会(瞄准) 1)通过隔离和分发已故和在世的胰岛来支持U19上的项目1和2 供全胰腺移植或自体胰腺移植的食蟹猴供体；以及 (目的2)为将要用于移植的胰岛提供体外和体内质量控制服务。一个 项目1共建议移植12个同种异体猴胰岛，其中胰岛将从 供体猴安乐死后的整个胰腺。胰岛将在培养前24小时进行培养 移植。年，项目2共进行了24例胰腺部分切除和胰岛隔离手术。 其中的胰岛将从70%的胰腺部分切除后处理并在以下条件下移植回供者 肾胶囊净化后立即服用。需要额外分离9个猴子胰岛来测试新的批次 对于胶原酶和中性蛋白酶，将对整个U19进行总共45个猴子胰岛的分离 在资助期内。为了更好地解释胰岛移植的结果并能够比较 不同实验性胰岛移植组在衡量胰岛移植成功率方面的结果 对于胰岛移植物保护的耐受性诱导，关键是建立内部控制系统，以确保 用于移植研究的胰岛是可行的和功能的，以及在不同的 每个项目内的试验组。我们建议使用标准化的方法，包括体外和体外。 活体观察与同种异体和自体移植相关的猴胰岛 功效。包括胰岛等效性计算、样本纯度估计、葡萄糖刺激胰岛素 用于评估免疫缺陷小鼠的释放、细胞死亡检测和边缘胰岛质量移植 胰岛在体内发挥作用。总而言之，小岛核心将为这两个项目提供专家技术服务 这一应用通过提供大量、高质量和良好特性的纯化猴胰岛来实现 每一次移植的个人捐赠者。此外，我们将提供咨询，以制定使用 核心的最佳服务和解决可能出现的问题。最重要的是，我们预计 拟议的处理和鉴定猴胰岛细胞的服务目标将促进 这款U19上的杰出研究人员正在进行治疗1型糖尿病的研究。

Core Summary This U19 proposal aims to achieve islet transplant tolerance in the setting of deceased (Project 1) and living (Project 2) donor transplantation. Both of these projects rely on the use of single cynomolgus monkey donor islets in transplantation tolerance studies. Further, islet processing for studies in Project 2 is especially challenging, as it requires sufficient quantity and quality of islets from partial pancreatectomy to restore glucose control. The main service aim of this centralized Islet Isolation, Quality Control, and Transplantation Core Facility for the U19 is to serve as a reliable resource for high quality monkey islets needed for islet transplantation in Projects 1 and 2, allowing consistent experimental results. We will (Aim 1) support Projects 1 and 2 on this U19 by isolating and distributing islets from deceased and living cynomolgus monkey donors for allo- or auto-transplantation using whole or partial pancreas, respectively; and (Aim 2) provide in vitro and in vivo quality control services on the islets that will be used for transplantation. A total of 12 allogeneic monkey islet transplants are proposed for Project 1 in which islets will be isolated from whole pancreata of donor monkeys after they are euthanized. Islets will be cultured for 24 hours prior to the transplant. A total of 24 partial pancreatectomy and islet isolation procedures will be performed for Project 2 in which islets will be processed from 70% partial pancreatectomy and transplanted back to the donor under kidney capsule immediately after purification. With additional 9 monkey islet isolations needed to test new lots of collagenase and neutral protease, a total of 45 monkey islet isolations for the entire U19 will be performed during the funded period. In order to better interpret the islet transplant outcomes and to be able to compare the results generated from different experimental islet transplantation groups in measuring the success of tolerance induction for islet graft protection, it will be critical to establish an internal control system to ensure all islets used for the transplant studies are viable and functional, as well as comparable between the different experimental groups within each project. We propose to utilize standardized measures, both in vitro and in vivo, to characterize the isolated monkey islets for correlation with allogeneic and autologous transplantation efficacy. These include islet equivalence calculation, sample purity estimation, glucose stimulated insulin release, cell death detection, and a marginal islet-mass transplantation in immunodeficient mice for evaluating islet function in vivo. In summary, the Islet Core will provide the expert technical services for both projects on this application by providing large quantity, high quality, and well-characterized purified monkey islets from individual donors for each transplant. In addition, we will provide consultation to develop strategies for using the services of the Core optimally and for solving problems that may arise. Most importantly, we anticipate the proposed service aims of processing and characterizing monkey islet cells will facilitate the ability of the outstanding investigators on this U19 to conduct research toward a cure for Type 1 diabetes.