Table 1.
A summary of the major experimental and clinical studies investigating the relationship of TRAIL with T1DM in animal models and humans.
| First Author (Year of Publication) |
Experimental Model or Study Population | TRAIL-Related Intervention (If Applicable) |
Study Methods | Key Findings |
|---|---|---|---|---|
| Animal data | ||||
| Lamhamedi-Cherradi (2003) | NOD mice challenged with cyclophosphamide Normal and TRAIL-deficient C57BL/6 mice treated with multiple low doses of streptozotocin |
Soluble TRAIL receptor (sDR5) to block TRAIL function TRAIL gene knockout |
Induction of diabetes, production of recombinant human sDR5, ELISA, histochemistry, quantification of islet inflammatory lesions, cell cultures, analyses of cell viability and apoptosis | Accelerated diabetes onset ↑ severity of autoimmune insulitis in pancreatic islets ↑ GAD65-specific immune responses ↑ incidence and extent of islet inflammation in TRAIL-deficient mice |
| Mi (2003) | NOD mice challenged with cyclophosphamide NOD mice receiving diabetogenic spleen T-cells from newly-diagnosed diabetic NOD mice |
Soluble TRAIL receptor (sDR5) to block TRAIL function | Induction of diabetes, production of recombinant human sDR5, splenic T-cell isolation and proliferation assays, T-cell adoptive transfer, cell cultures, gene expression profiling of pancreatic islets, analyses of cell viability and apoptosis, ELISA, immunoblotting | ↑ incidence of cyclophosphamide-induced T1DM ↑ incidence and earlier onset of T1DM post-transfer of diabetogenic T-cells |
| Dirice (2009) | Rats treated with multiple low doses of streptozotocin | Adenovirus-mediated TRAIL gene delivery into pancreatic islets (Ad5hTRAIL) | Ex vivo genetic engineering of pancreatic β-cells, transplantation of genetically modified pancreatic islets in streptozotocin-induced diabetic rats, metabolic assays, ELISA, pancreas histology | Prolonged normoglycemia ↓ severity of insulitis Extended islet graft survival and function |
| Zauli (2010) | C57BL/6 mice treated with multiple low doses of streptozotocin | Recombinant TRAIL treatment (intraperitoneal injections) for 5 days In vitro exposure of human/mouse PBMCs and isolated human islets to recombinant TRAIL |
Islet isolation, cell cultures, RNA and protein analyses, metabolic assays, ELISA, pancreas histology | ↓ hyperglycemia ↑ body weight ↑ insulin secretion Partially preserved islet morphology and function ↓ TNF-α, ↓ OPG, ↓ VCAM-1 expression in TRAIL-treated mice ↑ SOCS1 expression in PBMCs and human islets exposed in vitro to TRAIL |
| Kang (2010) | NOD mice | Adenovirus-mediated systemic human TRAIL gene delivery (iv injection) | Metabolic assays, cell cultures, RNA extraction and RT-PCR in pancreas and liver, pancreatic islet isolation and histopathological analysis, cell viability and flow cytometry apoptosis assays, Western blot analysis, ELISA for plasma cytokine and TIMP-1 measurements, gelatin zymography for the inhibition of MMPs | ↓ hyperglycemia ↑ TIMP-1 expression ↓ pancreatic MMP activity ↓ cytokine-induced insulitis and apoptosis Prevention of T1DM development |
| Clinical data | ||||
| Tornese (2014) | 507 pediatric subjects n = 387 patients with T1DM n = 98 healthy controls n = 22 healthy AA-positive subjects |
NA | Retrospective study ELISA for serum soluble TRAIL measurements |
↓ serum soluble TRAIL levels in T1DM vs. other groups ↓ serum soluble TRAIL levels in T1DM patients presenting with DKA at onset (vs. those without DKA) Inverse correlation between serum TRAIL levels at diagnosis and insulin requirements up to 2 years of follow-up |
| Tornese (2015) | n = 11 pediatric patients with newly diagnosed T1DM complicated by DKA and secondary DKA | NA | Pilot study ELISA for serum soluble TRAIL measurements at sequential time points after admission, blood gas analysis for metabolic status assessment |
↑ serum soluble TRAIL levels shortly after insulin administration and metabolic stabilization Inverse correlation between serum TRAIL levels and the degree of metabolic decompensation |
Abbreviations: AA-positive: autoantibody-positive; DKA: diabetic ketoacidosis; ELISA: enzyme-linked immunosorbent assay; GAD65: glutamic acid decarboxylase 65; iv: intravenous; MMPs: matrix metalloproteinases; NA: not applicable; NOD: non-obese diabetic; OPG: osteoprotegerin; PBMCs: peripheral blood mononuclear cells; RT-PCR: reverse transcriptase polymerase chain reaction; sDR5: soluble death receptor 5; SOCS1: suppressor of cytokine signaling 1; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; TIMP-1: tissue inhibitor of metalloproteinase 1; TNF-α: tumor necrosis factor-α; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; VCAM-1: vascular cellular adhesion molecule-1.