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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：
10019062
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/10019062
关键词：
Allogenic Animal Model Animals Antigens Autoimmune Process 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

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.

项目总结