Approximately 24 million Americans suffer from diabetes, a devastating chronic disease with no known cure. However, islet cell transplantation has been shown to be a promising treatment and possible cure. There are still major challenges to overcome in making this treatment standard therapy. Low success rate of islet isolation, necessity for multiple donor organs and difficulty in maintaining insulin-free status are the major issues to be resolved. In this study, we will apply unique methods to improve both quantity and quality of isolated human islets. If this approach is successful, we will obtain high quantity and quality of human islets, therefore resolving these major issues. Based on our preliminary data, ductal injection of modified HL solution increased islet yield more than 3 times compared with our standard method. In addition, based on our other preliminary data, HMGB1 is uniquely high in islets and this HMGB1 acts as inflammatory cytokines which deteriorates isolated islets. Therefore we hypothesized that the combination of modified HL solution with anti-HMGB1 for ductal preservation will substantially improve the results of islet isolation. We propose two aims as follows;
Aim 1 : To compare modified HL solution and Kyoto solution for ductal preservation. For this aim, we will perform pancreatic ductal preservation using either Kyoto solution or modified HL solution at procurement site. The pancreata will be brought to our GMP facility for islet isolation. Then, we will isolate islets and assess those islets using standard (based on the Edmonton protocol) and extensive (gene microarray analysis, HMGB1 measurement) assessments.
Aim 2 : To identify the efficacy of anti-HMGB1 antibody for ductal preservation. For this aim, we will perform pancreatic ductal preservation with or without anti-HMGB1 antibody at procurement site. The process and assessment is the same as aim1. We have already established ductal preservation method, clinical islet isolation and islet transplantation. We also routinely perform standard islet assessment. In addition, we have established our unique extensive assessment including microarray analysis of isolated islets and HMGB1 measurement in islets. Therefore the proposed project is ready to start. Since we have an established clinical islet transplantation program at Baylor, the results from these experiments will be immediately applied in the clinical field. . We believe this research will overcome major challenges facing islet cell transplantation;thereby achieving a milestone in advancing islet transplantation from experimental treatment to standard therapy. Furthermore, this research will be the next step toward a cure for diabetes.

Public Health Relevance

Approximately 24 million Americans suffer from diabetes, a devastating chronic disease with no known cure. Islet transplantation has been shown to be a promising treatment and potential cure for diabetes. Critical to the success of islet transplantation is obtaining a high quantity and quality of islets from donor pancreata. Recently we found that our new pancreatic ductal preservation method substantially improved the quantity and quality of isolated islets. This proposed study will focus on identifying the best ductal preservation solution in order to maximize the quantity and quality of isolated islets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK090513-02
Application #
8207223
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$196,000
Indirect Cost
$71,000
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Naziruddin, B; Iwahashi, S; Kanak, M A et al. (2014) Evidence for instant blood-mediated inflammatory reaction in clinical autologous islet transplantation. Am J Transplant 14:428-37
Kanak, Mazhar A; Takita, Morihito; Itoh, Takeshi et al. (2014) Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-?B inhibitors. Transplantation 98:578-84
Takita, Morihito; Itoh, Takeshi; Shimoda, Masayuki et al. (2014) Pancreatic ductal perfusion at organ procurement enhances islet yield in human islet isolation. Pancreas 43:1249-55
Takita, Morihito; Itoh, Takeshi; Matsumoto, Shinichi et al. (2013) Autoimmune chronic pancreatitis with IgG4-related pancreatic pseudocyst in a patient undergoing total pancreatectomy followed by autologous islet transplantation: a case report. Pancreas 42:175-7
Itoh, T; Iwahashi, S; Shimoda, M et al. (2011) High-mobility group box 1 expressions in hypoxia-induced damaged mouse islets. Transplant Proc 43:3156-60