title: Deletion of STAT-1 pancreatic islets protects against streptozotocin-induced diabetes and early graft failure but not against late rejection.
abstract: OBJECTIVE
  Exposure of beta-cells to inflammatory cytokines leads to apoptotic cell death through the activation of gene networks under the control of specific transcription factors, such as interferon-gamma-induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that beta-cells lacking STAT-1 are resistant to cytokine-induced cell death in vitro. The aim of this study was to investigate the effect of STAT-1 elimination on immune-mediated beta-cell destruction in vivo.
  
  
  METHODS
  Multiple low-dose streptozotocin (STZ) was given to C57BL/6 mice after syngeneic STAT-1(-/-) or wild-type islet transplantation. STAT-1(-/-) and wild-type islets were also transplanted in alloxan-diabetic BALB/c and spontaneously diabetic nonobese diabetic (NOD) mice. Additionally, mice were treated with interleukin (IL)-1 blockade (IL-1 receptor antagonist [IL-1ra]) and low-dose T-cell suppression (cyclosporine A [CsA]).
  
  
  RESULTS
  When exposed to multiple low-dose STZ in an immune-competent host, STAT-1(-/-) islets were more resistant to destruction than wild-type islets (28 vs. 100% diabetes incidence, P < or = 0.05). STAT-1 deletion also protected allogeneic islet grafts against primary nonfunction in autoimmune NOD mice (0 vs. 17% using wild-type islets). However, no difference in survival time was observed. Additionally, treating recipients with IL-1ra and CsA prolonged graft survival in chemically diabetic BALB/c mice, whereas no difference was seen between STAT-1(-/-) and C57BL/6 grafts.
  
  
  CONCLUSIONS
  These data indicate that STAT-1 is a key player in immune-mediated early beta-cell dysfunction and death. When considering the many effector mechanisms contributing to beta-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of beta-cell survival in the autoimmune context of type 1 diabetes.
authors.affiliation: Laboratory of Experimental Medicine and Endocrinology, Campus Gasthuisberg O&N 1, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Hanne I
authors.initials: HI
authors.lastname: Callewaert
authors.forename: Conny A
authors.initials: CA
authors.lastname: Gysemans
authors.forename: Laurence
authors.initials: L
authors.lastname: Ladrière
authors.forename: Wannes
authors.initials: W
authors.lastname: D'Hertog
authors.forename: Julianna
authors.initials: J
authors.lastname: Hagenbrock
authors.forename: Lutgart
authors.initials: L
authors.lastname: Overbergh
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000494:pharmacology; D015996:Survival Rate; D013997:Time Factors
chemical_list: D053583:Interleukin-1beta; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D013311:Streptozocin; D000496:Alloxan