ISLET-KIDNEY TRANSPLANTS FOR TREATMENT OF DIABETIC ESRD

描述(由申请人提供)： 胰岛移植在逆转糖尿病高血糖方面不如全器官胰腺移植有效。这种差异的主要原因之一可能是胰岛在受体体内重新血运重建所需的时间内因缺血损伤而丢失。在此基础上，我们在将复合器官移植到切除胰腺的小型猪体内前2-3个月，通过在肾被膜下移植自体胰岛来制备复合“胰岛肾”(IK)。研究发现，对于胰腺切除的受者，移植IKS可立即恢复正常血糖，并长期维持肾和胰岛功能。我们的数据还表明，单个活的供体胰腺含有足够的胰岛，以支持这种无血管的IK供体和受者的长期胰岛素需求。这项R33提案的目标是：1)了解IK相对于猪的游离胰岛提供这种显著优势的机制；2)将这些研究扩展到非人类灵长类动物体内的IK功能研究，作为治疗糖尿病合并终末期肾脏疾病的临床前模型。具体地说，我们将：1)分析在实现成功的胰岛功能方面，带血管的IK相对于游离胰岛移植的优势的原因；2)利用小型猪模型的遗传学，确定MHC配型在通过IK移植物成功逆转糖尿病方面的相对重要性；3)建立狒狒的IK移植模型，并评估同种异体IK移植对糖尿病狒狒高血糖的逆转能力；以及4)开发非侵入性的胰腺部分切除、IK的准备和移植中的IK移除技术。为这种“床到床”方法而组建的研究团队包括：1)移植生物学研究中心的基础科学家，2)马萨诸塞州总医院参与移植和糖尿病研究的临床医生，以及3)拥有与将要开发的技术相关的杰出专业知识的顾问。我们预计，使用预血管胰岛作为复合胰岛-肾移植的一部分，可能为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): Pancreatic islet transplantation is less efficient than whole organ pancreas transplantation in reversing the hyperglycemia of diabetes. One of the major reasons for this disparity may be the loss of islets to ischemic injury during the time it takes for the islets to revascularize in the recipient. On this basis, we have prepared composite "islet kidneys" (IK) by transplantation of autologous islets under the kidney capsule 2-3 months prior to transplantation of the composite organ into pancreatectomized miniature swine. Transplantation of IKs was found to restore euglycemia to pancreatectomized recipients immediately, and to maintain both renal and islet functions long-term. Our data also indicate that a single living donor pancreas contains sufficient islets to support the long-term insulin requirements of both the donor and recipient of such a prevascularized IK. The goals of this R33 proposal are: 1) to understand of the mechanism by which IK provide this marked advantage over free islets in swine; and 2) to extend these studies to in vivo functional studies of IK in non-human primates as a preclinical model for treatment of diabetic patients with end-stage renal disease. Specifically, we will: 1) Analyze the factors responsible for the advantage of vascularized IK over free islet transplants in achieving successful islet function; 2) Utilize the genetics of the miniature swine model to determine the relative importance of MHC matching in achieving successful reversal of diabetes by IK grafts; 3) Establish an IK transplantation model in baboons and assess the ability of allogeneic IK transplantation to reverse hyperglycemia in diabetic baboons; and 4) Develop non-invasive techniques for partial pancreatectomy, preparation of IK and IK removal for transplantation. The research team assembled for this "bench-to-bedside" approach includes: 1) basic scientists in the Transplantation Biology Research Center, 2) clinicians at the Massachusetts General Hospital involved in transplantation and diabetes research, and 3) consultants with outstanding expertise related to the techniques to be developed. We anticipate that the use of pre-vascularized islets as part of a composite islet-kidney transplant may provide a new and effective treatment modality for patients with class I diabetes and end-stage renal disease.