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）：本提案的总体目标是在狒狒中通过异体屏障同时诱导对肾脏和胰岛移植的耐受性。本研究基于以下观察结果：1)通过短疗程的大剂量他克莫司可以使小型幼年猪对完全错配的同种异体肾移植产生耐受，初步数据表明该方法在幼年狒狒身上也取得了成功；2)与游离胰岛移植相比，复合“胰岛肾”（I-K）是在移植前2个月将猪自体胰岛在肾包膜下移植到去肾、去胰的异体受者体内，可立即恢复正常血糖，并长期维持肾脏和胰岛功能；3)通过诱导混合造血嵌合，可以在成年动物中实现对同种异体肾移植的耐受。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制定临床相关的治疗方案。具体而言，我们将：1)建立幼年狒狒肾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耐受诱导方案中狒狒耐受和排斥反应的关系；3)观察胰岛-肾脏复合移植对经STZ治疗糖尿病的切除肾幼狒狒的糖尿病和肾功能衰竭的治疗效果；4)通过混合嵌合方法将I-K移植治疗糖尿病和肾衰竭扩展到使用耐受性诱导的成年狒狒，并评估Aim 2中开发的耐受性诱导的生物和分子生物标志物的有效性，以评估耐受性诱导。我们预计，在这些方法中结合耐受性诱导和血管化前胰岛的使用可以为I型糖尿病和终末期肾脏疾病患者提供一种新的有效的治疗方式。