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.

100多万美国人患有I型(胰岛素依赖型)糖尿病。移植人胰岛，在适当的免疫抑制下，可以提供长期的无胰岛素治愈。然而，可用的人类胰岛捐赠者严重短缺，每年仅够进行约1000例移植。此外，慢性免疫抑制可能会将这一应用排除在儿童身上。移植供体猪的胰岛可以解决 短缺。然而，在目前的技术下，需要增加免疫抑制来防止排斥反应。 Ximerex公司已经开发出移植猪异种移植的技术，同时消除了严重的免疫抑制。通过将来自预定受体的淋巴细胞移植到将成为供体的胎猪体内，移植前在供体猪体内实现了免疫耐受和组织适应的移植目标。受体免除了与严重免疫抑制相关的风险。 在一项初步研究中，我们用猪胰岛移植治愈了两只糖尿病恒河猴(全胰腺切除术)。他们接受了最低限度的移植前免疫抑制，没有移植后的抑制。长期异种胰岛移植 为两个接受者提供了无胰岛素状态。 使用这项受专利支配地位保护的优质技术，Ximerex公司将为医疗中心提供从嵌合供体猪制备的用于移植的胰岛和脾细胞。 这项提案将扩展、开发技术，并完成临床试验所需的明确的临产前研究。具体目标是： 目的1.确定导致猪异种移植接受时间延长的供体因素。 将确定特异性免疫耐受和猪组织适应在延长猪胰岛异种移植接受度中的相对作用。将确定胰岛的临界剂量。 目的2.改进猪胰岛样细胞团(PLCC)移植物以获得最快的健壮起效 正常血糖。 移植的猪胰岛细胞团的成熟通常被观察到延迟。胰岛的功能 移植物将得到加强，目标是加速成熟，从而治愈他们的糖尿病。 目的3.开发可供组织捐献的可证明来源猪群。 Ximerex更愿意接触到一群独特的生物医用级猪，监测47种潜在的病原体。这个 羊群将适当地开发用于初步临床试验。 目的4.制定移植后评估胰岛细胞和免疫能力的方案 将开发改善猪胰岛功能和受体免疫能力的方法。这将允许更早地发现排斥反应或移植物失败，并就人畜共患感染或机会性感染的风险确定异种移植的安全性。