TOLERANCE TO COMPOSITE ISLET-KIDNEY TRANSPLANTS IN BABOONS

狒狒对复合胰岛肾移植的耐受性

• 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
• 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

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在狒狒中同种异体屏障的肾脏和胰岛移植同时诱导耐受性。这些研究基于以下先前的观察结果：1）在少年微型猪中可以通过短暂的高剂量克莫司群在少年微型猪中实现对完全不匹配的肾脏同种异体移植的耐受性，而初步数据表明，这种方法在少年狒狒中也成功。 2）与游离胰岛移植物，复合“胰岛肾”（I-K）相反，在将复合器官移植到肾脏胶囊下两个月之前，通过移植自体猪胰岛在肾脏胶囊下进行了鲜明对比，并将其恢复了胰腺的pancectomectomectomepormia和Islet interment; 3）通过诱导混合造血嵌合体，可以在成年动物中实现对肾脏同种异体移植的耐受性。我们在这里建议将这些研究扩展到狒狒对I-K的耐受性，目的是为终止型糖尿病性肾病制定临床相关的治疗方案。具体而言，我们将：1）在少年狒狒中建立非人类同种异体耐受性的非人类灵长类动物模型； 2）评估生物学和分子标记物与经过公差诱导方案的狒狒的耐受性和排斥相关性； 3）测试复合胰岛 - 基德尼移植的能力，可以通过STZ治疗使肾切除型少年狒狒治疗糖尿病和肾衰竭； 4）通过混合嵌合治疗方法，通过I-K移植向成年狒狒进行糖尿病的治疗和肾衰竭，并评估AIM 2在AIM 2中开发的耐受性诱导的生物学和分子生物标志物的有效性，以评估耐受性诱导。我们预计，在这些方法中，耐受性诱导和血管前胰岛的使用结合可以为I型糖尿病和终末期肾脏疾病的患者提供一种新的有效治疗方式。