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: 10395586
• 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/10395586
• 关键词: Allogenic; Animal Model; Animals; Antigens; Autoimmune; Autologous; Blood Vessels; 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; 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; 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 这个实验室以前已经开发出一种移植胰岛的技术，作为复合材料的一部分。 胰岛-肾(I-K)，其中自体胰岛被放置在供体动物6至8的肾被膜下 移植前几周。在这段时间内，胰岛变得血管化，因此没有 当I-K随后被移植到受体动物身上时，胰岛的缺血性损伤。也没有 在此期间由于免疫反应造成的损害，因为胰岛是自体的。我们已经证明了 与游离胰岛移植相比，该技术在同种异体胰岛移植中的优势。 无论是在小型猪身上还是在非人类灵长类动物身上。然而，这种方法在临床胰岛中的适用性 移植受到6至8周血管形成的要求的限制，因为这一要求限制了 对活体捐赠者的方法。将该方法扩展到I-K异种移植可以消除这一限制， 为许多终末期糖尿病肾病患者目前未得到满足的需求提供治疗。直到 然而，最近异种移植肾的存活时间太短，需要的免疫抑制太大。 该方法被认为是一种可行的临床选择。我们最近的研究表明，从长远来看， 利用小型猪供体和诱导耐受性，猪肾在狒狒体内存活是可能的 接近。因此，该项目的目标是开发临床相关的耐受诱导策略。 用于猪到狒狒的I-K移植。具体来说，我们将：1)将IK技术与我们的MIXED 嵌合体耐受诱导方法确定肾脏耐受性是否延伸到猪胰岛和 逆转糖尿病；2)将IK和VTL技术结合起来，确定肾脏的耐受性是否延伸到 猪胰岛和逆转糖尿病；3)比较和对比混合嵌合体和VTL方法 关于对肾脏和胰岛抗原的耐受机制。如果成功，我们的方法可以克服 目前通过提供几乎无限的供体供应来治疗这一临床重要实体的局限性 胰岛和肾脏，一种耐受的方法，以避免需要长期、慢性免疫抑制和 来自近亲交配的小型猪的供体肾脏，其内在能力可达到与人类相似的大小 收件人。