Background: Because type 1 diabetes (T1D) results from the T cell-mediated destruction of the insulin-producing pancreatic beta cells, the depletion of the autoreactive T cells via apoptosis represents a viable strategy for the prevention of autoimmune diabetes. The functional role TNF Related Apoptosis Inducing Ligand (TRAIL), a novel member of TNF superfamily, in autoimmune diabetes remains unknown. To understand this, TRAIL function was counteracted by an injection of soluble TRAIL receptor into NOD mice, which enhanced the degree of autoimmune inflammation in pancreatic islets and facilitated the onset of diabetes. Second, the delivery of multiple low-doses of STZ into TRAIL-deficient mice resulted in a higher degree of islet inflammation and an earlier onset of diabetes. All these results suggested that exogenous TRAIL expression in pancreatic islets may have beneficial results in the setting of type 1 diabetes by virtue of its potential to retaliate against the assault by CTL.
Methods: Fluorometric measurements revealed optimum doses of adenovirus vectors to transduce pancreatic islets. Ad5hTRAIL vector was used to overexpress TRAIL in islet cells. Cytotoxicity of TRAIL overexpression was assessed using Annexin V staining. Ad5hTRAIL or AdLacZ-transduced rat pancreatic islets were transplanted under the kidney capsule of STZ-induced diabetic rats. The diabetic status after islet transplantation was followed up for 90 days.
Results: No adverse event of TRAIL overexpression was detected in islet cells in vitro. Forty mg/kg per BW of STZ derived from the consideration of both blood glucose levels and survival rates, successfully induced T1D in rats. Histopathologic analysis of our transplantation set up demonstrated that non-infected and AdLacZ-infected islet grafts were heavily infiltrated with mononuclear cells following transplantation. In contrast, Ad5hTRAIL infected islets displayed non/minimal mononuclear cell infiltration.
Conclusion: Only adenovirus mediated TRAIL gene delivery suppressed lymphocyte infiltration in islet transplanted sites and prolonged normoglycemia in STZ induced diabetic rats.
25 - 29 Apr 2009
European Society of Endocrinology