Islet Transplantation with Chimeric Donor Pigs

超过100万美国人患有I型（胰岛素依赖型）糖尿病。在适当的免疫抑制下，人类胰岛移植可以提供长期的无胰岛素治疗。然而，人类胰岛供体严重短缺，每年仅足以进行约1000次移植。此外，慢性免疫抑制可能排除对儿童的这种应用。供体猪胰岛移植可解决胰岛移植后的胰岛功能障碍。 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，Inc.已经开发出了一种技术，可以移植猪异种移植物，同时消除了严重的免疫抑制。通过将来自预期受体的淋巴细胞移植到注定成为供体的胎猪内，在移植之前，在供体猪内实现了免疫耐受和组织适应的移植目标。接受者避免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，没有移植后抑制。长期异种胰岛移植 为两个接受者提供无胰岛素状态。 Ximerex，Inc.利用这项受主导专利地位保护的专有技术，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。 该提案将扩展开发技术并完成临床试验所需的确定性临床前研究。具体目标是： 目标1。确定延长猪异种移植物接受的供体因素。 将确定特异性免疫耐受和猪组织调节在延长猪胰岛异种移植物接受中的相对作用。将确定胰岛的临界剂量。 目标2.改善猪胰岛样细胞簇（PlCC）移植物，以获得最快的稳健起效 真的。 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 移植物将被增强，目标是加速成熟，从而治愈他们的糖尿病。 目标3。开发一个可认证的来源猪群用于组织捐赠。 Ximerex优先使用独特的生物医学级猪群，监测47种潜在病原体。的 将适当开发牛群用于初始临床试验。 目标4。制定移植后胰岛细胞和免疫能力评估方案 将开发用于猪胰岛功能和受体免疫能力的改进方法。这些将允许早期检测排斥反应或移植失败，并确定异种移植在人畜共患病或机会性感染风险方面的安全性。

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.