LOCAL EXPRESSION OF IMMUNOREGULATORY IL-12P40 GENE PROLONGED SYNGENEIC ISLET GRAFT-SURVIVAL IN DIABETIC NOD MICE

Local production of immunosuppressive cytokines will be one of the mos t suitable therapeutic strategies against organ-specific autoimmune di abetes. To establish such a new therapy, we constructed recombinant ad enoviral vectors with inserted mIL-12p40 (Ad.IL-12p40) and mIL-10 (Ad. IL-10). Sufficient amounts of IL-12p40 and IL-10 were secreted by rele vant adenovirus-transfected nonobese diabetic (NOD) islets. Shortly af ter transfection, 400 NOD islets transfected with Ad.IL-12p40 or Ad.IL -10 were transplanted under the renal capsule of a newly diabetic NOD mouse. NOD mice with IL-12p40-producing islet grafts kept normoglycemi a in all of 14 grafted mice for over 4 wk after transplantation. In co ntrast, NOD mice with IL-10-producing islet grafts became diabetic in all of six grafted mice within 2 wk after transplantation. Reverse tra nscription-PCR analysis revealed that local production of IL-12p40 led to the decrease of interferon-gamma and the augmentation of transform ing growth factor-p at the graft site. These results suggest that IL-1 2 plays an important role in the destruction of islet cells at the inf lamed site of autoimmunity. Such a local blockade of IL-12 would be a useful gene therapy for human autoimmune diabetes.