A preclinical model of pig islet xenotransplantation as treatment for type 1 diabetes

这个多学科项目的目标是开发猪胰岛素分泌组织的来源，用于治疗1型糖尿病患者。目前，受益于胰岛移植的糖尿病患者数量远远超过任何人类胰岛组织来源。经过基因改造以避免排异反应和提高存活率的猪可以克服供体短缺的问题。我们相信，通过对猪胰岛素分泌组织进行适当的基因改造，可以避免异种成像时出现的攻击性排斥反应，并在没有胰岛素的情况下提供正常的血糖控制。这个项目集中在猪胰岛素分泌组织用于糖尿病患者之前需要克服的五个主要问题。它们是：确定胰岛素分泌组织的最佳来源；成人胰岛，新生儿或胎儿胰岛细胞群；克服对猪组织的强烈排斥反应；确定安全有效的免疫抑制方案；生产一种新型的转基因猪，这种猪将提供适用于人类的胰岛组织；并证明猪胰岛移植不会对患者或社区造成不当的感染风险。这项真正的合作项目资助汇集了一大批在糖尿病、胰岛移植、异种移植、猪转基因和猪遗传学方面有着强大研究记录的研究人员，其中包括照顾糖尿病患者的科学家和临床医生。将使用独特的猪资源，包括转基因猪，这些猪已被证明可以避免与移植猪组织相关的一些排斥机制。有一个圈养的狒狒群提供了一种独特的糖尿病模型。一个世界级的猪转基因设施已经被招募来产生新的转基因猪系，因为新的数据在小组内产生。最后，由于国家胰腺移植单位的参与，任何经证实的治疗策略都可以迅速进入临床试验。

The object of this multi-disciplinary program grant is to develop a source of pig insulin secreting tissue that will be used to treat type 1 diabetic patients. At present the number of diabetic patients that would benefit from islet transplantation far outnumber any human source of this tissue. Pigs that have been genetically altered to avoid rejection and enhance survival could overcome this donor shortage problem.. It is our belief that with the appropriate genetic modification pig insulin-secreting tissue can avoid the aggressive rejection response that occurs with xenographs and provide normal blood glucose control without insulin. This project concentrates on the five main issues that need to be overcome before pig insulin-secreting tissue can be used in diabetics. These are: identifying the best source of insulin secreting tissue to use; adult islets, newborn or foetal islet cell clusters; overcoming the strong rejection response to pig tissue; identifying a safe and effective immunosuppressive regime; producing a new types of genetically modified pigs that will provide islets tissue that will work in humans; and demonstrating that pig islet transplantation will not pose undue infective risks for the patient or community. This truly collaborative program grant has brought together a large group of investigators with strong research records in diabetes, islet transplantation, xenotransplantation, pig transgenesis and pig genetics and includes scientists and clinicians who look after diabetic patients. Unique pig resources will be used including genetically manipulated pigs that have been shown to avoid some of the rejection mechanisms associated with transplanting pig tissue. There is a captive-bred baboon colony that provided a unique model of diabetes. A world class pig transgenesis facility has been enlisted to generate new lines of genetically altered pigs as new data is produced within the group. Finally because of the involvement of the National Pancreas Transplant Unit any proven therapeutic strategy can be brought quickly to clinical trials.