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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该实验室此前已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)，其中将自体胰岛置于供体动物的肾囊下 6 至 8 移植前几周。在此期间，胰岛变得血管化，因此不存在随后将 I-K 移植到受体动物体内时，胰岛会出现缺血性损伤。也没有由于胰岛是自体的，因此在此期间由于免疫反应而造成损伤。我们已经证明了该技术相对于成功的同种异体胰岛移植的游离胰岛移植的优点，无论是小型猪还是非人类灵长类动物。然而，这种方法对临床胰岛的适用性移植受到血管化要求 6 至 8 周的限制，因为这一要求限制了活体捐赠者的方法。将方法扩展到 I-K 异种移植可以消除这种限制，为许多终末期糖尿病肾病患者目前未满足的需求提供治愈方法。直到然而最近，异种移植肾的存活时间太短，并且需要太大的免疫抑制该方法被视为可行的临床选择。我们最近的研究表明，长期来看使用微型猪供体和耐受诱导剂可以使狒狒体内的猪肾存活方法。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 技术与我们的混合技术相结合嵌合耐受诱导方法，以确定肾脏耐受是否延伸至猪胰岛和逆转糖尿病； 2）结合IK和VTL技术来确定肾脏的耐受性是否延伸至猪胰岛并逆转糖尿病； 3) 比较和对比混合嵌合和 VTL 方法关于对肾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，一种耐受方法，以避免需要长期、慢性免疫抑制和来自近交小型猪的供体肾脏，具有达到与人类相似大小的内在能力收件人。