TOLERANCE TO COMPOSITE ISLET-KIDNEY TRANSPLANTS IN BABOONS

描述（由申请方提供）：本提案的总体目标是在狒狒中诱导对跨越同种异体屏障的肾和胰岛移植物同时耐受。这些研究是基于以下先前的观察：1）幼年小型猪通过短期高剂量他克莫司治疗可以实现对完全不匹配的同种异体肾移植的耐受，初步数据表明这种方法在幼年狒狒中也是成功的; 2）与游离胰岛移植物相比，复合“胰岛肾”（I-K），通过在将复合器官移植到肾切除、胰腺切除的同种异体受体中之前两个月将自体猪胰岛移植到肾包膜下来制备，立即恢复正常并长期维持肾和胰岛功能;和3）通过诱导混合造血嵌合体，可以在成年动物中实现对肾同种异体移植物的耐受。我们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）在幼年狒狒中建立肾同种异体移植耐受性的非人灵长类动物模型; 2）评估生物和分子标记物与经历耐受诱导方案的狒狒中的耐受性和排斥的关联; 3）测试复合胰岛-肾移植物在肾切除的幼年狒狒中治疗糖尿病和肾衰竭的能力，所述幼年狒狒通过STZ治疗而患糖尿病;和4）通过混合嵌合体方法使用耐受诱导，通过I-K移植将糖尿病和肾衰竭的治疗扩展至成年狒狒，并评估目标2中开发的耐受诱导的生物和分子生物标志物用于评估耐受诱导的有效性。我们预计，在这些方法中，耐受诱导和预血管化胰岛的使用相结合，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.