Deletion of STAT-1 pancreatic islets protects against streptozotocin- induced diabetes and early graft failure but not against late rejection

Abstract

OBJECTIVE - Exposure of β-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-γ-induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that β-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 β-cell destruction in vivo. RESEARCH DESIGN AND 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 ≤ 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 β-cell dysfunction and death. When considering the many effector mechanisms contributing to β-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of β-cell survival in the autoimmune context of type 1 diabetes. © 2007 by the American Diabetes Association.