Neonatal porcine islet xenografts for the treatment of type 1 diabetes

在美国，1型糖尿病(T1 DM)影响着150多万人。胰岛细胞移植是一种有效的 治疗T1 DM，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 供体器官的来源和猪到人的异种胰岛移植可以为T1 DM提供一种可扩展的治疗方法 异种胰岛排斥反应能否得到可靠和可耐受的控制。异种移植排斥反应可通过以下方法减轻 受体免疫抑制和预防排斥所需的免疫抑制负担可能是 通过捐赠者对用于移植的胰岛进行基因改造而减少的。在本供资期间 (U01AI090956)，我们已经取得了实质性的进展，利用这两种方法建立了异种- 新生猪胰岛移植到糖尿病恒河猴体内的模型 证明了NPI可以在灵长类动物中提供扩展的胰岛功能。我们进一步开发了一种可容忍的 使用临床上可用的免疫抑制剂的免疫管理方案和一种新的方法，即Dual 胰岛移植模型(DITM)，以验证供体胰岛改变，以改善胰岛弹性、植入和 生死存亡。这些研究为异种胰岛排斥反应提供了重要的机制见解，尤其是 与靶向B细胞和Th17细胞功能有关。我们还提出了一种新的胰岛修饰，X-Linked 凋亡抑制因子(XIAP)过表达，可减少胰岛细胞凋亡，提高胰岛对T细胞的弹性。 体外介导性攻击。通过其他研究，我们已经确定了一种供体细胞疗法，即乙基碳二亚胺疗法。 脾细胞(ECDI-SP)输注，在小鼠中减少了免疫抑制的需要。在这股洋流中 竞争续订申请，我们提出了三个具体目标：1)优化我们的可访问性 免疫抑制方案，在我们最新见解的指导下，控制异种移植中B细胞和Th17的贡献 排斥反应；2)将我们关于ECDI-SP输注的最新见解从小鼠模型转化为猪到灵长类动物 模型，研究这种疗法减轻免疫抑制负担的可能性；以及3)检查 DITM中的胰岛修改，使用合理考虑的来自行业合作者和 具体检测XIAP在体内胰岛细胞存活中的作用。我们经验丰富且富有成效的团队是 在两位新合作者、胰岛移植和免疫调节专家罗迅荣博士的支持下， 世卫组织与柯克博士和eGenesis共同加入，eGenesis是一个通过 CRISPR方法学。我们的最终目标是确定理想的供体胰岛来源和临床可耐受的 免疫抑制方案促进异种胰岛移植治疗T1 DM的临床应用。

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.