Molecular mechanisms of death ligand-mediated immune modulation: a gene therapy model to prolong islet survival in type 1 diabetes.
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.
Sanlioglu
Ahter Dilsad
AD
Human Gene Therapy Unit and the Department of Medical Biology and Genetics, Akdeniz University, Faculty of Medicine, 07070 Antalya, Turkey.
Griffith
Thomas S
TS
Omer
Abdulkadir
A
Dirice
Ercument
E
Sari
Ramazan
R
Altunbas
Hasan Ali
HA
Balci
Mustafa Kemal
MK
Sanlioglu
Salih
S
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
D053222:Fas Ligand Protein; D014409:Tumor Necrosis Factor-alpha