Alpha1 Anti-trypsin Enhances Islet Autograft Survival

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 DESCRIPTION (provided by applicant): A major challenge in islet transplantation is avoiding early islet destruction and primary nonfunction after intraportal islet infusion. Because of these issues, at least two donors are needed for one recipient to achieve euglycemia after allogeneic islet transplantation (for patients with type 1 diabetes, T1D), and only around 1/3 of patients become insulin-independent after autologous islet transplantation (for patients with chronic pancreatitis, CP). Currently, no interventional protocols are in place with the goal to increase th survival of islet graft following transplantation in patients receiving islet transplantation. Thus effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Alpha1 anti-trypsin (AAT) is a serine proteinase inhibitor that inhibits various enzymes including elastase, trypsin and others. AAT manifests strong anti-inflammatory and anti-apoptotic properties and promotes vascularization. AAT infusion during peritransplantation period protects islets from immune rejection and preserves islets/β cell function in mice, pigs, and non-human primates, as manifested in autologous, allogeneic and xenogeneic islet transplant settings. Given this framework, we plan to conduct a clinical study to evaluate the therapeutic effects of the human purified AAT, Prolastin-C (Grifols Inc), in the prevention of islet death and dysfunction in autologous islet transplantation for chronic pancreatitis patients at the Medical University of South Carolina. In this study, we will further validate the protective effects of AAT observed in mice intrahepatic islet transplantation models using human islets from cadaveric donors and CP patients, by evaluating the effect of AAT in abrogating proinflammatory injury, islet death, and delayed revascularization that might contribute to primary islet nonfunction and islet destruction post transplantation. Furthermore, we will assess the efficacy of AAT administration during peritransplantation period for the prevention of surgical diabetes and the improvement of glycemic control after total pancreatectomy and islet autotransplantation in CP patients. Having been used for the treatment of pulmonary emphysema for more than 25 years, AAT has excellent safety record. The islet autotransplantation model offers a unique opportunity to assess the direct effect of AAT on human islets in the absence of an immune response, recurrence of autoimmunity, and insulin resistance. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but can serve as a powerful platform on which to address the more complex allogeneic islet cell transplantation for patients with T1D.