INTERLEUKIN-4 OR INTERLEUKIN-10 EXPRESSED FROM ADENOVIRUS-TRANSDUCED SYNGENEIC ISLET GRAFTS FAILS TO PREVENT [beta] CELL DESTRUCTION IN DIABETIC NOD MICE 1.
Smith, Dean K. 2; Korbutt, Gregory S. 3; Suarez-Pinzon, Wilma L. 4; Kao, Dina 2; Rajotte, Ray V. 3,4; Elliott, John F. 2,5
64(7):1040-1049, October 15, 1997.
Background: We performed ex vivo adenoviral gene transfer in a mouse pancreatic islet transplant model to test the efficacy of this expression system. We then determined whether adenoviral-mediated expression of mouse interleukin (IL) 4 or IL-10 from transduced syngeneic islet grafts could prevent disease recurrence in diabetic nonobese diabetic (NOD) mice.
Methods: An adenoviral vector expressing [beta]-galactosidase (AdCMV[beta]Gal) was used to transduce BALB/c islets (2.5x103 plaque-forming units/islet), which were analyzed for glucose responsiveness, islet cell recovery, and efficiency of gene transfer. In vivo function and reporter gene expression were examined with AdCMV[beta]Gal-transduced islet grafts in alloxan-induced diabetic syngeneic recipients. Adenoviruses expressing either IL-4 or IL-10 were used in a similar fashion to infect NOD islets, which were characterized in vitro, as well as transplanted into diabetic syngeneic recipients.
Results: In vitro functional studies showed no significant difference between control or transduced islets, with 50 /-4% of AdCMV[beta]Gal-infected islet cells staining positive for [beta]-galactosidase. Transplant recipients became nomoglycemic within 48 hr after transplant, and, although [beta]-galactosidase expression decreased over time, it was detectable in the graft for up to 8 weeks. Despite the nanogram quantities of IL-4 or IL-10 produced/day from each graft equivalent in vitro, transduced and transplanted NOD islets failed to prevent disease recurrence.
Conclusions: These results suggest that adenoviruses are efficient for at least medium term gene expression from islets in vivo, but neither IL-4 nor IL-10 alone can prevent autoimmune disease recurrence in NOD mice.
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