title: Prevention of high-mobility group box 1-mediated early loss of transplanted mouse islets in the liver by antithrombin III.
abstract: BACKGROUND
  The low efficiency of pancreatic islet transplantation mainly because of the early loss of transplanted islets hampers its clinical application. Previously, we have shown in mice that the early loss of transplanted islets in the liver is caused by innate immune rejection in concert with dendritic cells, natural killer T cells, and neutrophils to produce interferon (IFN)-γ, which is triggered by high-mobility group box 1 (HMGB1) released from transplanted islets. We herein determined whether the HMGB1-mediated early loss of transplanted mouse islets is prevented by antithrombin (ATIII).
  
  
  METHODS
  The effect of ATIII on in vitro and in vivo HMGB1-stimulated IFN-γ production of hepatic mononuclear cells was examined. Then, the effect of ATIII on amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngeneic islets from a single donor was determined.
  
  
  RESULTS
  In vitro and in vivo IFN-γ production of mononuclear cells in the liver of mice in response to HMGB1 was suppressed by ATIII. Hyperglycemia of streptozotocin-induced diabetic mice receiving 200 syngeneic islets into the liver from a single donor was ameliorated with down-regulation of IFN-γ production of natural killer T cells and neutrophils in the liver when ATIII but not vehicle was administered once at the time of islet transplantation. The favorable effect of ATIII was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment.
  
  
  CONCLUSIONS
  These findings demonstrate that ATIII prevents HMGB1-mediated early loss of transplanted islets caused by innate immune rejection, suggesting a potential application of ATIII to improve efficiency of clinical islet transplantation.
authors.affiliation: Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Daibo
authors.initials: D
authors.lastname: Kojima
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mera
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nishinakamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Takako
authors.initials: T
authors.lastname: Ogata
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Shohta
authors.initials: S
authors.lastname: Kodama
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yasunami
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000494:pharmacology*; D015704:CD4 Antigens / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D024243:HMGB1 Protein / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016381:Islets of Langerhans Transplantation; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology; D013311:Streptozocin; D018180:Thrombomodulin / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D024243:HMGB1 Protein; D018180:Thrombomodulin; D013311:Streptozocin; D007371:Interferon-gamma; D000990:Antithrombin III