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 the 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/? 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.

Public Health Relevance

The goal of this study is to determine whether AAT therapy during peritransplantation period can enhance efficacy of islet autotransplantation in CP patients undergo TP-IAT. Results from these studies are not only urgently needed to improve the quality of life of CP patients, but can serve as a powerful platform on which to address the more complex allogeneic islet cell transplantation for patients with T1D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Arreaza-Rubin, Guillermo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) GRP94 Is an Essential Regulator of Pancreatic ?-Cell Development, Mass, and Function in Male Mice. Endocrinology 159:1062-1073
Wang, Mengmeng; Song, Lili; Strange, Charlie et al. (2018) Therapeutic Effects of Adipose Stem Cells from Diabetic Mice for the Treatment of Type 2 Diabetes. Mol Ther 26:1921-1930
Wang, Hongjun; Strange, Charlie; Nietert, Paul J et al. (2018) Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy. Stem Cells Transl Med 7:11-19
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy. Antioxid Redox Signal 28:1309-1322
Sun, Zhen; Gou, Wenyu; Kim, Do-Sung et al. (2017) Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice. Mol Ther 25:2490-2501
Song, Lili; Sun, Zhen; Kim, Do-Sung et al. (2017) Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function. Stem Cell Res Ther 8:192
Wang, Jingjing; Sun, Zhen; Gou, Wenyu et al. (2017) ?-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes 66:970-980
Dong, H; Zhang, Y; Wang, J et al. (2017) Regulator of G protein signaling 2 is a key regulator of pancreatic ?-cell mass and function. Cell Death Dis 8:e2821
Wang, Jingjing; Wang, Hongjun (2017) Oxidative Stress in Pancreatic Beta Cell Regeneration. Oxid Med Cell Longev 2017:1930261
Yan, Jun; Wang, Hongjun; Xu, Qian et al. (2010) Signal sequence is still required in genes downstream of ""autocleaving"" 2A peptide for secretary or membrane-anchored expression. Anal Biochem 399:144-6