Islet Transplantation with Chimeric Donor Pigs

嵌合供体猪的胰岛移植

• 批准号: 7116973
• 负责人: WILLIAM Edward BESCHORNER
• 金额: $ 100万
• 依托单位: XIMEREX, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116973
• 关键词: artificial immunosuppression; cell population study; enzyme linked immunosorbent assay; flow cytometry; immune tolerance /unresponsiveness; immunocytochemistry; immunologic memory; method development; mixed lymphocyte reaction test; pancreatic islet transplantation; southern blotting; swine; technology /technique development; transplantation immunology; xenotransplantation

More than 1 million Americans have type I (insulin dependent) diabetes. Transplantation of human islets, with the appropriate immune suppression, can provide a long-term insulin free cure. However, there is a severe shortage of human islet donors available, sufficient for only about 1000 transplants annually. Furthermore, chronic immune suppression could exclude this application to children. The transplantation of islets from donor pigs could resolve the shortage. However, with current technology, increased immune suppression would be needed to prevent rejection. Ximerex, Inc. has developed technology for transplantating pig xenografts while eliminating the need for severe immune suppression. By engrafting lymphocytes from the intended recipient within fetal pigs destined to become the donors, the transplant goals ofimmtme tolerance and tissue accommodation are achieved within the donor pig, prior to transplantation. The recipient is spared the risks associated with severe immune suppression. In a pilot study, we have cured two diabetic rhesus monkeys (total pancreatectomy) with pig islet transplants. They received minimal pretransplant immune suppression and no post-transplant suppression. The long term islet xenografts provided an insulin free state for both recipients. Using this propeitary technology, protected with a dominant patent position, Ximerex, Inc. would provide medical centers with islets and splenoeytes prepared from chimeric donor pigs for transplantation. This proposal will extend develop the technology and complete the definitive preelinical studies needed for clinical trials. The specific aims are to: Aim 1. Determine the donor factors responsible for prolonged pig xenograft acceptance. The relative roles of specific immune tolerance and pig tissue accommodation in prolonging pig islet xenograft acceptance will be determined. The critical dose of islets will be established. Aim 2. Improve Porcine Islet-Like Cell Cluster (PlCC)grafts to obtain the most rapid onset of robust euglycemia. A delay is typically observed in the maturation of the transplanted pig islet cell clusters. The function of the islet grafts will be enhanced with the goal of accelerating the maturation, leading to a cure of their diabetes. Aim 3. Develop a certifiable source herd of swine for tissue donation. Ximerex has preferred access to a unique herd of biomedical grade swine, monitored for 47 potential pathogens. The herd will developed appropriately for initial clinical trials. Aim 4. Develop protocols for post-transplant assessment of the islet cells and immune competence Improved methods for pig islet function and immune competence of the recipient will be developed. These will permit earlier detection of rejection or graft failure, and establish the safety of xenotransplantation with regards to risk of zoonotic or opportunistic infections.

超过100万美国人患有I型（胰岛素依赖性）糖尿病。通过适当的免疫抑制的人类胰岛移植可以提供长期无胰岛素治疗。但是，人类胰岛供体的严重短缺，每年仅需大约1000次移植。此外，慢性免疫抑制可以将这一应用不包括在儿童中。从供体猪的胰岛移植可以解决 短缺。但是，使用当前的技术，将需要增加免疫抑制以防止排斥。 Ximerex，Inc。开发了用于移植猪异种移植的技术，同时消除了严重的免疫抑制的需求。通过在注定要成为捐助者的胎猪中植入淋巴细胞，在移植之前，在供体猪内实现了IMMTME耐受性和组织适应的移植目标。接收者免除了与严重的免疫抑制有关的风险。 在一项试点研究中，我们用猪胰岛移植治愈了两只糖尿病恒河猴（总胰腺切除术）。他们获得了最低移植前的免疫抑制，没有移植后抑制。长期胰岛异种移植物 为两个接受者提供了无胰岛素的状态。 Ximerex，Inc。使用这种具有优势专利位置保护的Propoitary技术，将为医疗中心提供由嵌合供体猪制备的胰岛和脾脏，用于移植。 该提案将扩展开发技术，并完成临床试验所需的确定的预基研究。具体目的是： 目标1。确定负责长时间猪异种移植接受的供体因素。 将确定特异性免疫耐受性和猪组织可容纳在延长猪胰岛异种移植物接受中的相对作用。将建立胰岛的关键剂量。 AIM 2。改善猪胰岛样细胞簇（PLCC）移植物，以获得最快的稳定性开始 尤古西亚。 在移植的猪胰岛细胞簇的成熟中通常观察到延迟。胰岛的功能 随着加速成熟的目标，将增强移植物，从而可以治愈其糖尿病。 AIM 3。开发可认证的猪群来捐赠猪。 Ximerex优先使用了独特的生物医学级猪群，并监测了47种潜在病原体。这 牛群将适当开发用于初始临床试验。 目标4。制定胰岛细胞移植后评估和免疫能力的方案 将开发改进的猪胰岛功能的方法和受体的免疫能力。这些将允许早期检测到排斥或移植失败，并在人畜共患感染或机会性感染的风险方面确定异种移植的安全性。