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Molecular mechanisms of death ligand‐mediated immune modulation: A gene therapy model to prolong islet survival in type 1 diabetes
Author(s) -
Sanlioglu Ahter Dilsad,
Griffith Thomas S.,
Omer Abdulkadir,
Dirice Ercument,
Sari Ramazan,
Altunbas Hasan Ali,
Balci Mustafa Kemal,
Sanlioglu Salih
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21677
Subject(s) - islet , immune system , pancreatic islets , medicine , fas ligand , tumor necrosis factor alpha , diabetes mellitus , pancreas , immunology , genetic enhancement , transplantation , inflammation , type 2 diabetes , cytotoxic t cell , cancer research , apoptosis , endocrinology , programmed cell death , biology , gene , biochemistry , in vitro
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. J. Cell. Biochem. 104: 710–720, 2008. © 2008 Wiley‐Liss, Inc.