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Abstract

Type 1 diabetes (T1D), characterized by permanent destruction of insulin-producing beta cells, is lethal unless conventional exogenous insulin therapy or whole-organ transplantation is employed. Although pancreatic islet transplantation is a safer and less invasive method compared with whole-organ transplant surgery, its treatment efficacy has been limited by islet graft malfunction and graft failure. Thus, ex vivo genetic engineering of beta cells is necessary to prolong islet graft survival. For this reason, a novel gene therapy approach involving adenovirus-mediated TRAIL gene delivery into pancreatic islets was tested to determine whether this approach would defy autoreactive T cell assault in streptozotocin (STZ)-induced diabetic rats. To test this, genetically modified rat pancreatic islets were transplanted under the kidney capsule of STZ-induced diabetic rats, and diabetic status (blood sugar and body weight) was monitored after islet transplantation. STZ-induced diabetic rats carrying Ad5hTRAIL-infected islets experienced prolonged normoglycemia compared with animals grafted with mock-infected or AdCMVLacZ-infected islets. In addition, severe insulitis was detected in animals trans- planted with mock-infected or AdCMVLacZ-infected islets, whereas the severity of insulitis was reduced in animals engrafted with Ad5hTRAIL-infected islets. Thus, TRAIL overexpression in pancreatic islets extends allograft survival and function, leading to a therapeutic benefit in STZ-induced diabetic rats.

Hum Gene Ther Cover Image Adenovirus-Mediated TRAIL Gene (Ad5hTRAIL) Delivery into Pancreatic Islets Prolongs Normoglycemia in Streptozotocin-Induced Diabetic Rats.

Figure 9 Immunohistochemical analysis of islet allografts. Photomicrographs show insulin in rat islet allografts 15, 30, 60, and 90 days posttransplantation as indicated above each panel. Infection conditions (mock, AdCMVLacZ, or Ad5hTRAIL) are given to the left of each panel. The large images were taken at an original magnification of x200, and x100 magnifications are also provided for clarity inside each image. Color images available online at www.liebertonline.com=hum.

Figure 10 TRAIL expression in pancreatic islet allografts after transplantation. Photomicrographs were taken 15 and 90 days posttransplantation. Control indicates staining performed in the absence of primary antibody. Color images available online at www.liebertonline.com=hum.

In conclusion, Although eventual rejection of the allograft remains a problem to be solved, we have clearly demonstrated in this study that prolongation of islet allograft survival is achievable by ex vivo adenoviral-mediated TRAIL gene transfer. By this token, the use of gutless adenoviral or adeno-associated viral (AAV) vectors is expected to yield a longer therapeutic benefit in extending allograft survival and function.