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Deletion of STAT-1 Pancreatic Islets Protects Against Streptozotocin-Induced Diabetes and Early Graft Failure but Not Against Late Rejection

¹ Laboratory of Experimental Medicine and Endocrinology, Campus Gasthuisberg O&N, Catholic University of Leuven, Leuven, Belgium
² Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium

Address correspondence and reprint requests to Dr. Chantal Mathieu, Laboratory of Experimental Medicine and Endocrinology, Campus Gasthuisberg O&N 1, Catholic University of Leuven, Herestraat 49, Bus 902, B-3000 Leuven, Belgium. E-mail: chantal.mathieu{at}uz.kuleuven.ac.be

Abbreviations: CsA, cyclosporine A; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; IFN, interferon; iNOS, inducible nitric oxide synthase; IP-10, interferon-–inducible protein-10; PNF, primary islet nonfunction; STAT, signal transducer and activator of transcription; STZ, streptozotocin

OBJECTIVE—Exposure of ß-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-–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 (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 ß-cell dysfunction and death. When considering the many effector mechanisms contributing to ß-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of ß-cell survival in the autoimmune context of type 1 diabetes.

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