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人体器官供应极限之外的手段。具体而言，已经研究了从猪到灵长类动物的胰岛移植作为为1型糖尿病患者提供调节的内源性胰岛素的手段。为了实现这一策略，我们研究了新生猪胰岛（NPIs）移植到恒河猴，并证明移植的NPIs可以使糖尿病灵长类动物胰岛素不依赖于接近一年的时间内使用免疫调节策略，在相同的强度范围内用于临床胰岛同种异体移植。一般来说，我们的方法依赖于共刺激阻断作为基础方案来预防胰岛排斥反应。移植物存活率接近临床试验的水平。本申请进一步推进了我们的临床前研究，以将NPI异种移植改进为促进首次人体试验的策略。该项目侧重于3个主要的改进，每个改进都得到了广泛的初步研究的支持，并需要临床翻译。1)我们有新的数据表明NPI受到Gal特异性天然抗体的不利影响，并且来自Gal-KO动物的NPI比野生型胰岛移植更快并且存活显著更好。我们将严格审查的作用，半乳糖特异性抗体在阻碍移植和诱导排斥反应的NPI在恒河猴，和使用Gal-KO猪，以减少移植后的免疫抑制治疗的需要。2)虽然抗NPI T细胞反应似乎使用当前的疗法得到了很好的控制，但我们有新的数据表明，获得性和天然抗体反应对NPI的长期生存构成了重大威胁。因此，我们将严格调查控制NPI特异性抗体反应作为一个重要的变量，在定义成功的免疫调节方案。3)认识到需要将免疫调节治疗建立在临床可耐受药物的基础上，我们将优化NPI所需的抗排斥治疗方案，以便仅使用可转化药物，特别是避免使用CD 154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转化的方案。 相关性：1型糖尿病威胁着美国100多万人的生命。众所周知，胰岛移植可以恢复糖尿病患者的胰岛素依赖性，但器官供体的供应（约6000/年）与需要的患者数量相比黯然失色。该项目旨在确定一种临床上可翻译的胰岛异种移植策略，以促进胰岛移植而不受器官供应的限制。

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.