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DELETION OF STAT-1 IN PANCREATIC ISLETS PROTECTS AGAINST STREPTOZOTOCIN-INDUCED DIABETES AND EARLY GRAFT FAILURE BUT NOT AGAINST LATE REJECTION

Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Campus Gasthuisberg O&N, Catholic University of Leuven, Leuven (KUL), Belgium
Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium

Correspondence: chantal.mathieu{at}uz.kuleuven.ac.be

Objective:Exposure of ß-cells to inflammatory cytokines leads to apoptotic cell death through activation of gene networks under control of specific transcription factors, like interferon (IFN)--induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that ß-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 ß-cell destruction in vivo.

Research Design and Methods:Multiple low-dose streptozotocin (MLDS) 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 NOD mice. Additionally, mice were treated with IL-1-blockade (IL-1 receptor antagonist, IL-1ra) and low-dose T-cell suppression (cyclosporine A, CsA).

Results:When exposed to MLDS in an immune-competent host, STAT-1^–/– islets were more resistant to destruction than wild-type islets (28% versus 100% diabetes incidence, p0.05). STAT-1 deletion also protected allogeneic islet grafts against primary non-function in autoimmune NOD mice (0% versus 17% using wild-type islets). However, no difference in survival time was observed. Treating recipients additionally with IL-1ra and CsA prolonged graft survival in chemically-diabetic BALB/c mice, but again no difference was seen between STAT-1^–/– or C57BL/6 grafts.

Conclusions:These data indicate that STAT-1 is a key player in immune-mediated early ß-cell dysfunction and death. Considering the many effector mechanisms contributing to ß-cell death following islet transplantation, however, multiple combined interventions will be needed for prolongation of ß-cell survival in the autoimmune context of type 1 diabetes.

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