title: Pretreatment of donor islets with the Na(+) /Ca(2+) exchanger inhibitor improves the efficiency of islet transplantation.
abstract: Pancreatic islet transplantation is an attractive therapy for the treatment of insulin-dependent diabetes mellitus. However, the low efficiency of this procedure necessitating sequential transplantations of islets with the use of 2-3 donors for a single recipient, mainly due to the early loss of transplanted islets, hampers its clinical application. Previously, we have shown in mice that a large amount of HMGB1 is released from islets soon after their transplantation and that this triggers innate immune rejection with activation of DC, NKT cells and neutrophils to produce IFN-γ, ultimately leading to the early loss of transplanted islets. Thus, HMGB1 release plays an initial pivotal role in this process; however, its mechanism remains unclear. Here we demonstrate that release of HMGB1 from transplanted islets is due to hypoxic damage resulting from Ca(2+) influx into β cells through the Na(+) /Ca(2+) exchanger (NCX). Moreover, the hypoxia-induced β cell damage was prevented by pretreatment with an NCX-specific inhibitor prior to transplantation, resulting in protection and long-term survival of transplanted mouse and human islets when grafted into mice. These findings suggest a novel strategy with potentially great impact to improve the efficiency of islet transplantation in clinical settings by targeting donor islets rather than recipients.
authors.affiliation: Central Research Institute for Islet Biology, Fukuoka University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mera
authors.forename: T
authors.initials: T
authors.lastname: Itoh
authors.forename: S
authors.initials: S
authors.lastname: Kita
authors.forename: S
authors.initials: S
authors.lastname: Kodama
authors.forename: D
authors.initials: D
authors.lastname: Kojima
authors.forename: H
authors.initials: H
authors.lastname: Nishinakamura
authors.forename: K
authors.initials: K
authors.lastname: Okamoto
authors.forename: M
authors.initials: M
authors.lastname: Ohkura
authors.forename: J
authors.initials: J
authors.lastname: Nakai
authors.forename: T
authors.initials: T
authors.lastname: Iyoda
authors.forename: T
authors.initials: T
authors.lastname: Iwamoto
authors.forename: T
authors.initials: T
authors.lastname: Matsuda
authors.forename: A
authors.initials: A
authors.lastname: Baba
authors.forename: K
authors.initials: K
authors.lastname: Omori
authors.forename: J
authors.initials: J
authors.lastname: Ono
authors.forename: H
authors.initials: H
authors.lastname: Watarai
authors.forename: M
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Yasunami
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010647:Phenyl Ethers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D024243:HMGB1 Protein; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger
keywords: Early loss of transplanted islets; Na+/Ca2+ exchanger; hypoxia; islet transplantation