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扩展临床移植的手段，超出了人体器官供应的限制。具体来说，猪胰岛移植到灵长类动物已经被研究作为一种为1型糖尿病患者提供调节内源性胰岛素的手段。为了实现这一策略，我们研究了新生儿猪胰岛（npi）移植到恒河猴身上，并证明移植的新生儿猪胰岛可以使糖尿病灵长类动物在接近一年的时间内不依赖胰岛素，使用的免疫调节策略与临床胰岛异体移植的强度范围相同。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的基础方案。移植物的存活率正在接近临床试验的水平。目前的应用程序进一步我们的临床前研究，以完善NPI异种移植为促进首次人体试验的策略。该项目侧重于3个主要改进，每个改进都有广泛的初步研究支持，并需要临床转化。1)我们有新的数据表明npi会受到天然Gal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，存活率更高。我们将仔细研究gal特异性抗体在阻碍恒河猴npi移植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，我们将严格研究npi特异性抗体反应的控制，作为确定免疫调节方案成功的重要变量。3)认识到需要将免疫调节疗法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，以便仅使用可翻译的药物，特别是避免使用CD154和/或lfa -1特异性药物，并将广泛的准备工作固化为一种有助于临床翻译的方案。

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.