Neonatal Porcine Islet Xenografts for the Treatment of Type 1 Diabetes

 描述(申请人提供)：美国有150多万人患有1型糖尿病，每年新增确诊病例30,000例。它是由自身免疫破坏产生胰岛素的胰岛细胞引起的。通过直接移植来自供体胰腺的胰岛细胞，可以安全地完成这些？细胞的替换。 然而，对这种供体胰岛供应不足的依赖将继续限制其广泛应用。这一不足可以通过利用替代来源的胰岛来弥补，其中最有希望的是猪。我们实验室和其他研究小组的研究表明，将新生猪胰岛注入糖尿病非人类灵长类动物(NHP)，可逆转其高血糖，延长其存活时间。然而，在猪胰岛异种移植成为临床现实之前，仍有许多免疫学和技术挑战必须解决。以下标准是成功的关键 临床猪胰岛异种移植：1)治疗药物必须容易获得， 最小的副作用，2)猪的遗传操作和胰岛的体外治疗必须优化，以最大限度地减少与人类免疫系统的相互作用，以及3)必须定义和控制导致猪胰岛丢失的细胞移植特有的机制。我们在这一领域的丰富经验使我们开发了一种全面的翻译策略来解决这些问题，将这种潜在的治疗方法带入临床现实。三个目标是我们翻译战略的基础。我们的方法以经过验证的技术为中心，这些技术是我们合作伙伴关系中的标准实践，使我们能够追求具有实际设计的真正新颖的调查。拟议的独立但相互关联的研究为我们提供了同时调查每一项研究的机会。我们将通过一个经过验证和广泛使用的糖尿病临床前模型来完善临床上可用的免疫抑制药物。临床移植的另一个当务之急是使用我们为实现这一目的而开发的性别移植模型来识别“理想的”猪胰岛供者。我们将致力于确定潜在的外源性和内源性胰岛修饰，以改善移植物存活和功能。我们还将进一步阐明NFKB驱动的内在炎症和程序性细胞死亡途径，这些途径是胰岛植入和存活过程中不可或缺的。这些研究旨在克服异种胰岛移植临床应用的障碍，推进异种移植领域的发展。

 DESCRIPTION (provided by applicant): Type 1 diabetes afflicts more than 1.5 million people in the United States with 30,000 additional cases diagnosed each year. It is caused by autoimmune destruction of the insulin-producing pancreatic islet ß cells. Replacement of these ß cells can be accomplished safely by direct transplantation of islet cells from a donor pancreas, however the dependence on this inadequate supply of donor islets will continue to limit its broad application. This shortfall could be remedied by the utilization of islets from alternate sources, the most promising of which is the pig. Studies from our laboratory and other groups have demonstrated prolonged survival of neonatal porcine islets infused into diabetic non-human primates (NHPs) with reversal of their hyperglycemia. Nevertheless, there remain a number of immunologic and technical challenges that must be solved before porcine islet xenotransplantation becomes a clinical reality. The following criteria are essential for successful clinical porcine islet xenotransplantation: 1) the treatment agents must be readily available, with minimal side effects, 2) genetic manipulation of pigs and ex vivo treatment of islets must be optimized to minimize interaction with the human immune system, and 3) mechanisms unique to cellular transplantation that lead to porcine islet loss must be defined and controlled. Our extensive experience in this field has led us to develop a comprehensive translational strategy addressing these concerns to bring this potential therapy to clinical reality. Three Aims serve as the foundation for our translational strategy. Our approach is centered on proven techniques that are standard practice within our collaborative partnership, enabling us to pursue truly novel investigations with practical design. The proposed independent but interrelated studies provide us an opportunity to investigate each concurrently. We will refine clinically available immunosuppression with a proven and extensively used diabetic preclinical model. Also imperative to clinical translation is identification of the "ideal" porcine islet donor, using the ual transplant model we have developed to fulfill this purpose. We will work to define potential extrinsic and intrinsic islet modifications that may improve graft survival and function. We will also further elucidate the intrinsic NFKB-driven inflammation and programmed cell death pathways that are integral to the process of islet engraftment and survival. These studies aim to overcome barriers remaining to clinical application of islet xenotransplantation and advance the field of xenotransplantation.