TOLERANCE TO COMPOSITE ISLET-KIDNEY TRANSPLANTS IN BABOONS

狒狒对复合胰岛肾移植的耐受性

基本信息

批准号：
7292321
负责人：
DAVID H SACHS
金额：
$ 64.64万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-20 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7292321
关键词：
Adolescent Adult Allogenic Animals Antibody Formation Antigens Autologous Autologous Transplantation Biological Assay Biological Markers Biopsy Blood Calcineurin inhibitor Cells Child Chimerism Coculture Techniques Complement Data Development Diabetes Mellitus Diabetic Nephropathy Disease Dose End stage renal failure Family suidae Gene Expression Goals Hematopoietic Histology Human Immunosuppression In Vitro Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Kidney Kidney Failure Kidney Transplantation Macaca fascicularis Mediating Messenger RNA Methodology Miniature Swine Modality Modeling Molecular Nature Numbers Organ Pancreatectomy Papio Patients Phenotype Polymerase Chain Reaction Proteins Protocols documentation Renal Glycosuria Research Personnel Safety Staging Streptozocin T-Lymphocyte Tacrolimus Technology Testing Therapeutic immunosuppression Thymectomy Thymus Gland Time Tissue Grafts Tissues Transplantation Transplantation Tolerance Treatment Protocols aged base capsule clinical application clinically relevant cytokine cytotoxicity day diabetic granzyme B inhibitor/antagonist islet juvenile animal kidney allograft mature animal new technology nonhuman primate perforin peripheral blood research study response

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is the induction of tolerance simultaneously to both renal and pancreatic islet transplants across an allogeneic barrier in baboons. The studies are based upon the following previous observations: 1) tolerance to fully mismatched renal allografts can be achieved in juvenile miniature swine by a short course of high-dose tacrolimus, and preliminary data indicate that this methodology is also successful in juvenile baboons; 2) in contrast to free islet grafts, composite "islet kidneys" (I-K), prepared by transplantation of autologous swine islets under the kidney capsule two months prior to transplantation of the composite organ into nephrectomized, pancreatectomized allogeneic recipients, restore euglycemia immediately and maintain both renal and islet function long-term; and 3) tolerance to renal allografts can be achieved in adult animals by induction of mixed hematopoietic chimerism. We propose here to extend these studies to the induction of tolerance to I-K in baboons, with the intent of developing a clinically relevant treatment protocol for end stage diabetic nephropathy. Specifically, we will: 1) Establish a non-human primate model of renal allograft tolerance in juvenile baboons; 2) Assess the association of biologic and molecular markers with tolerance and rejection in baboons undergoing tolerance-induction protocols; 3) Test the ability of composite islet-kidney transplants to treat both diabetes and renal failure in nephrectomized, juvenile baboons, made diabetic through STZ treatment; and 4) Extend treatment of diabetes and renal failure by I-K transplantation to adult baboons using tolerance induction through a mixed chimerism approach and assess the validity of biologic and molecular biomarkers of tolerance induction developed in Aim 2 for assessment of tolerance induction. We anticipate that the combination of tolerance induction and the use of pre-vascularized islets in these approaches could provide a new and effective treatment modality for patients with type I diabetes and end-stage renal disease.

描述（由申请人提供）：该提案的总体目标是同时诱导狒狒跨同种异体屏障的肾和胰岛移植的耐受性。这些研究基于以下先前的观察结果：1）通过短疗程的大剂量他克莫司可以在幼年小型猪中实现对完全错配同种异体肾移植物的耐受，初步数据表明该方法在幼年狒狒中也取得了成功； 2) 与游离胰岛移植相比，复合“胰岛肾”（I-K）是在将复合器官移植到肾切除、胰腺切除的同种异体受者体内两个月前通过将自体猪胰岛移植到肾包膜下制备的，可立即恢复正常血糖并维持肾和胰岛的长期功能； 3)通过诱导混合造血嵌合可以在成年动物中实现对肾同种异体移植物的耐受。我们在此建议将这些研究扩展到诱导狒狒对 I-K 的耐受性，目的是为终末期糖尿病肾病开发临床相关的治疗方案。具体来说，我们将： 1）建立幼年狒狒肾同种异体移植耐受的非人灵长类动物模型； 2) 评估生物和分子标记与接受耐受诱导方案的狒狒耐受和排斥的关联； 3) 测试复合胰岛-肾脏移植治疗肾切除幼年狒狒（通过 STZ 治疗而患上糖尿病）的糖尿病和肾功能衰竭的能力； 4) 通过混合嵌合方法使用耐受诱导，通过 I-K 移植到成年狒狒来扩展对糖尿病和肾衰竭的治疗，并评估目标 2 中开发的耐受诱导生物和分子生物标志物的有效性，以评估耐受诱导。我们预计，在这些方法中将耐受诱导和使用预血管化胰岛相结合，可以为 I 型糖尿病和终末期肾病患者提供一种新的有效治疗方式。