TY - JOUR
T1 - Significant improvement in islet yield and survival with modified ET-Kyoto solution
T2 - ET-Kyoto/neutrophil elastase inhibitor
AU - Machida, Tomohiko
AU - Tanemura, Masahiro
AU - Ohmura, Yoshiaki
AU - Tanida, Tsukasa
AU - Wada, Hiroshi
AU - Kobayashi, Shogo
AU - Marubashi, Shigeru
AU - Eguchi, Hidetoshi
AU - Ito, Toshinori
AU - Nagano, Hiroaki
AU - Mori, Masaki
AU - Doki, Yuichiro
AU - Sawa, Yoshiki
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013
Y1 - 2013
N2 - Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.
AB - Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.
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U2 - 10.3727/096368912X637028
DO - 10.3727/096368912X637028
M3 - Article
C2 - 22472201
AN - SCOPUS:84873033039
VL - 22
SP - 159
EP - 173
JO - Cell Transplantation
JF - Cell Transplantation
SN - 0963-6897
IS - 1
ER -