Composite porcine islet-kidney xenotransplants to cure diabetes and renal failure

猪胰岛-肾复合异种移植治疗糖尿病和肾衰竭

• 批准号: 10597990
• 负责人: DAVID H SACHS
• 金额: $ 125.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597990
• 关键词: Allogenic; Animal Model; Animals; Antigens; Autoimmune Responses; Autologous; Bone Marrow; Bone Marrow Transplantation; Chimerism; Chronic; Clinical; Clinical Treatment; Data; Diabetes Mellitus; Diabetic Nephropathy; Disease; Donor person; Family suidae; Goals; Human; Hybrids; Immune response; Immunosuppression; Inbreeding; Insulin-Dependent Diabetes Mellitus; Ischemia; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Kidney Failure; Kidney Transplantation; Laboratories; Living Donors; Medical; Methodology; Methods; Miniature Swine; Modeling; Molecular; Morbidity - disease rate; Nature; Organ; Pancreas; Pancreas Transplantation; Pancreatectomy; Papio; Patients; Population; Predisposition; Prevalence; Protocols documentation; Regimen; Renal Glycosuria; Risk; Techniques; Technology; Testing; Therapeutic immunosuppression; Thymic epithelial cell; Thymus Gland; Time; Tissues; Toxic effect; Transgenic Organisms; Transplantation; Vascularization; Xenograft procedure; capsule; clinical application; clinically relevant; diabetic; experimental study; improved; innovation; islet; kidney xenograft; mortality; natural antibodies; new technology; nonhuman primate; pre-clinical; response; virtual

Project Summary This laboratory has previously developed a technique for transplanting pancreatic islets as part of a composite islet-kidney (I-K), in which autologous islets are placed under the kidney capsule of the donor animal 6 to 8 weeks prior to transplantation. During this time, the islets become vascularized, so that there is no period of ischemic damage to the islets when the I-K is subsequently transplanted to a recipient animal. There is also no damage due to an immune response during this period, since the islets are autologous. We have demonstrated the advantages of this technique over free islet transplantation for successful allogeneic islet transplantation, both in miniature swine and in non-human primates. However, the applicability of this approach to clinical islet transplantation is limited by the requirement for 6 to 8 weeks for vascularization, since this requirement limits the approach to living donors. Extension of the approach to I-K xenotransplants could eliminate this limitation, providing a cure for the currently unmet needs of many patients with end-stage diabetic nephropathy. Until recently, however, the survival of xenograft kidneys was too short and the immunosuppression required too great for the approach to be considered as a viable clinical option. Our recent studies now suggest that long-term survival of porcine kidneys in baboons is possible using miniature swine donors and a tolerance-inducing approach. The goal of this project is therefore to develop a clinically relevant tolerance induction strategy for pig-to-baboon I-K transplantation. Specifically, we will: 1) Combine IK technology with our mixed chimerism tolerance-inducing approach to determine whether tolerance of kidney extends to porcine islets and reverses diabetes; 2) Combine IK plus VTL technologies to determine whether tolerance of kidney extends to porcine islets and reverses diabetes; and 3) Compare and contrast mixed chimerism and VTL approaches with regard to mechanism of tolerance to kidney and islets antigens. If successful, our approach could overcome the current limitations to treatment of this clinically important entity by providing a virtually limitless donor supply of islets and kidneys, a tolerance approach to avoid the need for long-term, chronic immunosuppression and a donor kidney from inbred miniature swine, with intrinsic capacity to attain a size similar to that of human recipients.

项目摘要 该实验室以前已经开发了一种用于移植胰岛的技术，作为复合材料的一部分 伊斯特 - 凯尼（I-K），其中自体胰岛放在供体动物6至8的肾囊下 移植前几周。在此期间，胰岛变为血管化，因此没有时间 当I-K随后将I-K移植到受体动物时，胰岛的缺血损害。也没有 由于胰岛是自体的，因此在此期间因免疫反应而造成的损害。我们已经证明了 该技术比自由胰岛移植的优点用于成功的同种异体胰岛移植， 在微型猪和非人类灵长类动物中。但是，这种方法适用于临床胰岛 移植受血管形成6到8周的要求限制，因为该要求限制了 生物捐助者的方法。将方法扩展到I-K Xenotplastrant可以消除此限制， 为许多末期糖尿病性肾病患者的目前未满足的需求提供治愈。直到 然而，最近，异种移植肾的存活太短，免疫抑制需要太大 为了将方法视为可行的临床选择。我们最近的研究现在表明长期 使用微型猪供体和耐受性诱导的猪肾脏可以在狒狒中生存 方法。因此，该项目的目的是制定临床相关的耐受性诱导策略 用于猪至巴布恩I-K移植。具体来说，我们将：1）将IK技术与混合 促嵌合耐受性的方法来确定肾脏的耐受性是否延伸到猪胰岛和 逆转糖尿病； 2）结合IK加VTL技术，以确定肾脏的容忍度是否扩展到 猪胰岛并逆转糖尿病； 3）将混合嵌合和VTL方法与之进行比较和对比 关于对肾脏和胰岛抗原的耐受机制。如果成功的话，我们的方法可以克服 通过提供几乎无限的供体供应，目前对该临床重要实体的治疗局限 胰岛和肾脏，一种避免需要长期，慢性免疫抑制和A的耐受性方法 来自近交微型猪的供体肾脏，具有与人类相似的尺寸的内在能力 收件人。