TOLERANCE TO COMPOSITE ISLET-KIDNEY TRANSPLANTS IN BABOONS

描述(由申请人提供)：这项建议的总体目标是诱导对跨越同种异体屏障的巴布亚肾和胰岛移植的同时耐受。这些研究基于以下观察结果：1)通过短疗程的大剂量他克莫司治疗，幼年小型猪可获得对完全不匹配的异基因肾移植的耐受性，初步数据表明这种方法在幼年狒狒身上也是成功的；2)与游离胰岛移植物不同，复合“胰岛肾”(I-K)是通过将复合器官移植到肾切除、胰腺切除的异基因肾移植前两个月，通过诱导混合造血嵌合体诱导成年动物的肾移植耐受而获得的。在这里，我们建议将这些研究扩展到在狒狒中诱导对I-K的耐受，目的是为了开发一种临床上相关的终末期糖尿病肾病的治疗方案。具体地说，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物与耐受诱导方案之间的关联；3)测试复合胰岛肾移植治疗糖尿病和肾功能衰竭的能力；2)通过混合嵌合体方法使用耐受性诱导，并评估为评估耐受性诱导而开发的耐受性诱导生物和分子生物标记物的有效性。我们预计，在这些方法中，耐受诱导和预血运胰岛的使用相结合，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。

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.