Neonatal porcine islet xenografts for the treatment of type 1 diabetes

1型糖尿病（T1 DM）在美国影响超过150万人。胰岛细胞移植是一种有效的 但其使用受到人类供体胰腺短缺的严重限制。猪是一种潜在的 供体器官的来源，以及猪到人的胰岛异种移植可以为T1 DM提供可扩展的治疗 如果异种胰岛排斥反应能够得到可靠且可耐受的控制。异种移植排斥反应可以通过以下方式减轻： 接受者免疫抑制和防止排斥所需的免疫抑制负担可以 通过对用于移植的胰岛进行供体遗传修饰来减少。在当前供资期间 （U 01 AI 090956），我们已经取得了实质性的进展，利用这两种方法建立了一个异种- 使用新生猪胰岛（NPI）移植到糖尿病恒河猴的胰岛移植模型， 证明NPI可以在灵长类动物中提供扩展的胰岛功能。我们进一步发展了一种可以容忍的 免疫管理方案，使用临床可用的免疫抑制剂，和一种新的方法，双重 胰岛移植模型（DITM），以验证供体胰岛改变，改善胰岛弹性，植入和 生存这些研究为异种胰岛排斥反应提供了重要的机制见解， 与靶向B细胞和Th 17细胞功能相关。我们还提出了一种新的胰岛修饰，X-连锁 细胞凋亡抑制因子（XIAP）过表达，减少胰岛细胞凋亡并改善胰岛对T细胞的弹性， 介导的体外攻击。通过其他研究，我们已经确定了一种供体细胞疗法，乙基碳二亚胺处理 脾细胞（ECDI-SP）输注，这在小鼠中减少了对免疫抑制的需要。在当前的 竞争性续期申请，我们提出了三个具体目标，将：1）优化我们的可访问性 根据我们最近见解指导免疫抑制方案，以控制B细胞和Th 17对异种移植物的贡献 排斥反应; 2）将我们最近关于ECDI-SP输注的见解从小鼠模型转化为我们的猪到灵长类动物 模型，研究这种疗法减少免疫抑制负担的潜力;和3）检查 在DITM中进行胰岛修饰，使用来自行业合作者的合理考虑的转基因猪， 特别是检查XIAP在体内胰岛细胞存活中的作用。我们经验丰富的生产团队 在两位新合作者的支持下，胰岛移植和免疫调节专家罗勋荣博士， 他与柯克博士和eGenesis一起作为共同PI加入，eGenesis是一个通过 CRISPR方法。我们的最终目标是确定一个理想的供体胰岛来源和一个临床上可耐受的 免疫抑制方案将猪胰岛异种移植治疗T1 DM推向临床现实。

Type 1 diabetes (T1DM) affects more than 1.5 million people in the US. Islet cell transplantation is an effective treatment for T1DM but its use is critically limited by a shortage of human donor pancreata. Pigs are a potential source of donor organs, and pig-to-human islet xenotransplantation could provide a scalable therapy for T1DM if xeno-islet rejection could be reliably and tolerably controlled. Xenotransplant rejection can be mitigated by recipient immune suppression and the burden of immunosuppression required to prevent rejection can be reduced through donor genetic modification of the islets used for transplantation. In the current funding period (U01AI090956), we have made substantial progress, exploiting both of these approaches to establish a xeno- islet transplant model using neonatal porcine islets (NPIs) transplanted to diabetic rhesus monkeys and have demonstrated that NPIs can provide extended islet function in primates. We have further developed a tolerable immune management regimen that uses clinically available immunosuppressants, and a novel method, the dual islet transplant model (DITM), to validate donor islet alterations that improve islet resilience, engraftment and survival. These studies have provided important mechanistic insights into xeno-islet rejection, particularly related to targetable B cell and Th17 cell functions. We have also advanced a novel islet modification, X-linked inhibitor of apoptosis (XIAP) over-expression, that reduces islet apoptosis and improves islet resiliency to T cell– mediated attack in vitro. Through other study, we have identified a donor cell therapy, ethylcarbodiimide treated splenocyte (ECDI-SP) infusion, which in mice lessens the need for immunosuppression. In this current competitive renewal application, we propose three specific aims that will: 1) optimize our accessible immunosuppressive regimen, guided by our recent insights, to control B cell and Th17 contributions to xenograft rejection; 2) translate our recent insights regarding ECDI-SP infusion from murine models into our pig-to-primate model, investigating the potential for this therapy to reduce the burden of immunosuppression; and 3) examine islet modifications in the DITM, using rationally considered transgenic pigs from industry collaborators and specifically examining the role of XIAP in islet cell survival in vivo. Our experienced and productive team is bolstered by two new collaborators, Dr. Xunrong Luo, an expert in islet transplantation and immunomodulation, who joins as co-PI with Dr. Kirk, and eGenesis, a group rapidly advancing the genetic modification of pigs through CRISPR methodologies. Our ultimate goal is to identify an ideal donor islet source and a clinically tolerable immunosuppressive regimen to advance porcine islet xenotransplantation for T1DM into clinical reality.