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.
Porcine islet xenotransplantation is a promising treatment for type 1 diabetes (T1DM), provided that an appropriate genetically-modified donor pig can be identified, and a clinically available and tolerable immunosuppressive regimen can be developed to ensure successful engraftment and rejection-free survival of the transplanted islets. The overall goal of the proposed studies therefore is to use our established preclinical model of islet xenotransplantation to study strategies of porcine islet modifications and recipient immunomodulation that will promote porcine islet engraftment and survival. We hope to advance porcine islet xenotransplantation for T1DM from preclinical studies to clinical reality.
