title: 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.
authors.affiliation: Human Gene Therapy Unit and the Department of Medical Biology and Genetics, Akdeniz University, Faculty of Medicine, 07070 Antalya, Turkey.
authors.forename: Ahter Dilsad
authors.initials: AD
authors.lastname: Sanlioglu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
authors.forename: Abdulkadir
authors.initials: A
authors.lastname: Omer
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.forename: Ramazan
authors.initials: R
authors.lastname: Sari
authors.forename: Hasan Ali
authors.initials: HA
authors.lastname: Altunbas
authors.forename: Mustafa Kemal
authors.initials: MK
authors.lastname: Balci
authors.forename: Salih
authors.initials: S
authors.lastname: Sanlioglu
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000628:therapy*; D053222:Fas Ligand Protein / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007107:Immune System / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D014409:Tumor Necrosis Factor-alpha