Optimizing Pancreatic Islet Transplantation: A Translational Research Approach
Creators: Marfil Garza, Braulio Alejandro
Publisher: name: University of Alberta Library
Year: 2022

<p>Type 1 diabetes (T1D) is caused by autoimmune-mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. People with T1D need exogenous insulin to survive, but also to avoid complications from uncontrolled glycemia. Unfortunately, insulin treatment commonly causes hypoglycemia, which severely limits optimal glycemic control. While technological advances can ameliorate hypoglycemia, some people remain recalcitrant to the most advanced interventions and progress to severe hypoglycemia, hypoglycemia unawareness, and potentially, death. Pancreatic islet transplantation (ITx) corrects this dire scenario. In ITx, islets obtained from deceased-donor pancreata are infused into the recipient’s intraportal circulation using a percutaneous approach. While ITx has progressed substantially, long-term outcomes to optimize patient care are scarce. Additionally, although ITx enables abrogation of hypoglycemia, improvements in glycemic control and, in many cases, insulin independence, it is not a cure in its current form, predominantly because patients require lifelong immunosuppression to avoid immune rejection. Hence, strategies to attain immunosuppression-free ITx are necessary. <br>
This thesis presents studies contributing to enhance informed shared decision-making in clinical ITx, but also introduces experimental strategies to circumvent lifelong immunosuppression post-transplant. Each chapter provides context for the problem being addressed and detailed methodology to evaluate the strength of our conclusions. <br>
In the first chapter, long-term outcomes with ITx are evaluated by analyzing the 20-year experience at our center. Patient survival post-transplant is &gt;90%, which is reassuring in the context of chronic immunosuppression. Indeed, while immunosuppression-related complications are common, these have no impact on patient survival. Graft survival rates are ~50% at 20-years post-transplant, and insulin independence is achieved in 80% of patients, although 20-year insulin independence rates are only 8%. Improvements in glycemic control and measures of hypoglycemia are observed throughout follow-up. Finally, an exploratory analysis shows that the use of anakinra plus etanercept for &gt;1 islet infusion and a BETA-2 score &gt;15 within 1-year post-first transplant increases the odds of maintaining graft survival. <br>
The second chapter evaluates whether ITx and whole pancreas transplantation (PTx) have similar mortality, morbidity, and metabolic benefits. Over a 20-year period, we show that ITx and PTx have similar patient survival, however, ITx has shorter hospital lengths-of-stay, and fewer procedural complications and hospital readmissions. Conversely, insulin independence rates and glycemic control were better with PTx. <br>
Chapter three explores extrahepatic ITx. While safe, intraportal ITx can cause bleeding and thrombosis sporadically. Thus, alternative “extrahepatic” implantation sites are desirable. Herein, a comparative analysis shows that extrahepatic ITx does not support islet engraftment compared to intraportal ITx. This occurs across all evaluated extrahepatic sites (omentum, subcutaneous space or gastric submucosa). Importantly, patients having intraportal ITx after a failed extrahepatic transplant show similar outcomes to those undergoing upfront intraportal ITx. <br>
These studies address relevant issues to inform clinical practice and identify opportunities to optimize ITx. The next chapters propose two experimental strategies to enable immunosuppression-free ITx. <br>
Chapter four studies the potential of regulatory T cells (Treg) in preventing immune rejection after ITx. Herein, we use antibodies directed at the tumor necrosis factor receptor superfamily member 25 (TNFR25), which is intrinsically expressed by Tregs. We demonstrate that antibody-mediated agonistic stimulation substantially expands endogenous Tregs, and that a single injection of TNFR25-antibodies prior to transplantation significantly prolonged graft survival in a mouse model of allogeneic ITx. This approach circumvents the need for ex vivo Treg expansion, a complex and costly procedure that limits clinical translation. <br>
Chapter five presents a sequential approach harnessing controlled inflammation-induced neovascularization to create a subcutaneous cavity that supports optimal function of customized islet encapsulation devices. This study builds on two successful strategies previously introduced by the Shapiro and Ma laboratories. This combinatorial approach enabled diabetes reversal in syngeneic, allogeneic, and xenogeneic murine models without the use of immunosuppression. Human islet survival was also observed in an immunocompetent xenogeneic islet transplant model. Notably, we demonstrate that impaired devices can be readily replaced in situ into the existing vascularized cavity, with prompt return to normoglycemia. Finally, we present protocols to guide scalability of our approach using a minipig model. <br>
These experimental studies introduce two promising platforms to support immunosuppression-free clinical ITx.<br>
Beyond current limitations, β-cell replacement therapies represent a hope for a true cure for T1D. The clinical and experimental perspectives presented in this thesis contribute to achieving this goal.</p>