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). Poor islet graft engraftment after transplantation contributes to the low efficacy of islet transplantation. Alpha-1 antitrypsin (AAT) is a serine proteinase inhibitor that manifests strong anti-inflammatory and anti- apoptotic properties and promotes vascularization. AAT infusion during the peri-transplantation period protects islets from immune rejection and preserves islets/? cell function in mouse, pig, and non-human primate, as manifested in autologous, allogeneic and xenogeneic islet transplant settings. Our parent award was designed to study the mechanistic effect of the human purified AAT, Prolastin-C (Grifols, US) when human islets are transplanted into the diabetic NOD-SCID mice, and to conduct a clinical study to evaluate the therapeutic effects of AAT in the prevention of islet cell death and dysfunction in CP patients undergoing total pancreactectomy and islet autotransplantation (TP-IAT), in a double blind, randomized and controlled study (www.clinicaltrials.gov, NCT02947087). Data from our animal study suggest that AAT increases islet graft survival by suppressing instant blood mediated inflammation reaction (IBMIR), macrophage activation and inflammation after intraportal islet transplantation. In the clinical trial, we have enrolled 24 of 48-targeted patient enrollments. However, no mechanistic studies in human samples were proposed in the parent award to confirm the mechanistic data obtained from the animal studies. Since we are still actively recruiting the last 24 patients to achieve the enrollment goal, we propose additional studies to directly address a gap between our animal studies and the clinical studies by testing the impact of AAT on patients' peripheral blood mononuclear cells (PBMCs), cytokine profiles and ? cell death during the peri-transplantation period. We hypothesize that AAT treatment increases ? cell survival by changing PBMC profiles and/or gene expressions, and consequently reduces inflammation that may contribute to islet death post transplantation. We estimate that these additional studies will reveal critical information on the mechanistic effects of AAT in human islet transplantation settings.

Public Health Relevance

The goal of this study is to collect more patient samples and analyze them to gain mechanistic insights on the protective effects of AAT in chronic pancreatitis patients undergoing total pancreatectomy and islet transplantation. The extra data gained will greatly increase the parent award's overall impact by providing a more comprehensive and rich picture of AAT therapy in the context of a highly novel and innovative clinical intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK105183-04S1
Application #
9827176
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
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
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
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
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