Neonatal Porcine Islet Xenografts for the Treatment of Type 1 Diabetes

描述(由申请人提供)：异种移植已被提议作为一种将临床移植扩展到超出人体器官供应限制的手段。具体地说，从猪到灵长类动物的胰岛移植已经被作为一种为1型糖尿病患者提供调节内源性胰岛素的手段进行了研究。为了实现这一策略，我们研究了将新生猪胰岛(NPI)移植到恒河猴体内，并证明了移植的NPI可以使糖尿病灵长类动物在接近一年的时间内使用与临床同种异体胰岛移植相同强度的免疫调节策略，使胰岛素独立一年。总的来说，我们的方法依赖于共刺激阻断作为预防胰岛排斥反应的基础方案。移植物存活率正在接近临床试验所能达到的水平。目前的应用进一步促进了我们的临床前研究，将NPI异种移植改进为一种促进首次人体试验的策略。该项目专注于3项主要改进，每一项都得到了广泛的初步研究的支持，并为临床翻译所需。1)我们有新的数据表明，NPI受到针对Gal的天然抗体的不利影响，来自Gal-KO动物的NPI移植更快，存活明显好于野生型胰岛。我们将严格研究Gal特异性抗体在阻止NPI在恒河猴体内植入和诱导排斥反应中的作用，以及使用Gal-KO猪来减少移植后免疫抑制治疗的需要。2)尽管使用目前的治疗方法抗NPI T细胞反应似乎得到了很好的管理，但我们有新的数据表明，获得性抗体和自然抗体反应对NPI的长期生存构成了重大威胁。因此，我们将严格研究NPI特异性抗体反应的控制，将其作为确定免疫调节方案成功与否的重要变量。3)认识到免疫调节治疗需要建立在临床耐受药物的基础上，我们将优化NPI所需的抗排斥方案，以便只使用可翻译的药物，特别是避免使用CD154和/或LFA-1特异性药物，并将大量的准备工作固化为有助于临床翻译的方案。 相关性：1型糖尿病威胁着美国100多万人的生命。众所周知，胰岛移植可以使糖尿病患者恢复胰岛素独立，但器官捐赠者的供应(约6000/年)与需要治疗的患者数量相比相形见绌。本项目旨在为异种胰岛移植定义一种临床可翻译的策略，以促进不受器官供应限制的胰岛移植。

DESCRIPTION (provided by applicant): Xenotransplantation has been proposed as a means of extending clinical transplantation beyond the limits of the human organ supply. Specifically, islet transplantation from pigs to primates has been investigated as a means of providing regulated endogenous insulin for patients with type 1 diabetes. In pursuit of this strategy, we have studied the transplantation of neonatal porcine islets (NPIs) into rhesus monkeys and demonstrated that transplanted NPIs can render diabetic primates insulin independent for periods approaching a year using immunomodulatory strategies that are within the same scope of intensity as those used for clinical islet allotransplantation. Our approach has, in general, relied upon costimulatory blockade as a base regimen to prevent islet rejection. Graft survival is approaching that which would enable of a clinical trial. The present application furthers our pre-clinical studies to refine NPI xenotransplantation into a strategy facilitating a first in man trial. The project focuses on 3 major refinements, each supported by extensive preliminary study and required for clinical translation. 1) We have new data indicating that NPIs are adversely influenced by natural antibody specific for Gal and that NPIs derived from Gal-KO animals engraft quicker and survive significantly better than wild type islets. We will examine critically the role of Gal-specific antibodies in impeding engraftment and inducing rejection of NPIs in rhesus monkeys, and the use of Gal-KO pigs to reduce the need for immunosuppressive therapy post transplant. 2) Although anti-NPI T cell responses appear well managed using current therapies, we have new data indicating that acquired and natural antibody responses pose a significant threat to long-term NPI survival. We thus will investigate critically the control of NPI-specific antibody responses as an important variable in defining the success of an immunomodulatory regimen. 3) Recognizing the need to base immunomodulatory therapies on clinically tolerable agents, we will optimize the anti-rejection regimen required for NPIs so as to solely utilize translatable agents, particularly avoiding the use of CD154 and/or LFA-1-specific agents and solidifying an extensive body of preparative work into a regimen that will facilitate clinical translation. RELEVANCE: Type 1 diabetes threatens the lives of over 1 million people in the United States. Islet transplantation is known to restore insulin independence to patients with diabetes, but the supply of organ donors (~6000/year) is eclipsed by the number of patients in need. This project seeks to define a clinically translatable strategy for islet xenotransplantation to facilitate islet transplantation without the limits of organ supply.