Molecular mechanisms of death ligand‐mediated immune modulation: A gene therapy model to prolong islet survival in type 1 diabetes

Abstract

Type 1 diabetes results from the T cell-mediated destruction of pancreatic beta cells. Islet transplantation has recently become a potential therapeutic approach for patients with type 1 diabetes. However, islet-graft failure appears to be a challenging issue to overcome. Thus, complementary gene therapy strategies are needed to improve the islet-graft survival following transplantation. Immune modulation through gene therapy represents a novel way of attacking cytotoxic T cells targeting pancreatic islets. Various death ligands of the TNF family such as FasL, TNF, and TNF-Related Apoptosis-Inducing Ligand (TRAIL) have been studied for this purpose. The over-expression of TNF or FasL in pancreatic islets exacerbates the onset of type 1 diabetes generating lymphocyte infiltrates responsible for the inflammation. Conversely, the lack of TRAIL expression results in higher degree of islet inflammation in the pancreas. In addition, blocking of TRAIL function using soluble TRAIL receptors facilitates the onset of diabetes. These results suggested that contrary to what was observed with TNF or FasL, adenovirus mediated TRAIL gene delivery into pancreatic islets is expected to be therapeutically beneficial in the setting of experimental models of type 1 diabetes. In conclusion; this study mainly reveals the fundamental principles of death ligand-mediated immune evasion in diabetes mellitus.

Therapeutic potential of VIP vs PACAP in diabetes

“…Natural immune cells and Th1 cytokines (Sanlioglu et al 2008b) play key roles in the generation of inflammation causing pancreatic tissue damage during the early phase of T1D (Sanlioglu et al 2008a). As VIP can skew the proinflammatory cytokine profile to an anti-inflammatory response, the extent to which VIP has any therapeutic effect on autoimmune model of diabetes has been tested.…”

High TRAIL Death Receptor 4 and Decoy Receptor 2 Expression Correlates With Significant Cell Death in Pancreatic Ductal Adenocarcinoma Patients

“…One of the therapeutic genes, which has currently been evaluated in the context of gene therapy, is tumor necrosis factorYrelated apoptosis-inducing ligand (TRAIL). 9 TRAIL is a type II membrane protein that can bind to 5 different receptors: TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), and osteoprotegrin. 10 DR4 and DR5 are the death receptors that signal for apoptosis, whereas DcR1, DcR2, and osteoprotegrin are considered antagonistic because they are unable to induce such signaling because of the lack of intracellular death domain or are secreted molecules.…”

Treatment With Recombinant Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alleviates the Severity of Streptozotocin-Induced Diabetes

“…While a large amount of data are available about tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) as an anticancer agent (1), some studies have suggested a potential role of endogenous TRAIL in type 1 diabetes (2–4). When TRAIL function was blocked through the systemic administration of a soluble TRAIL receptor into NOD mice, the onset of diabetes was significantly increased, and the degree of autoimmune inflammation was augmented in pancreatic Langerhans islets as a result of TRAIL blockage (2,3).…”