title: Local expression of immunoregulatory IL-12p40 gene prolonged syngeneic islet graft survival in diabetic NOD mice.
abstract: Local production of immunosuppressive cytokines will be one of the most suitable therapeutic strategies against organ-specific autoimmune diabetes. To establish such a new therapy, we constructed recombinant adenoviral 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 relevant adenovirus-transfected nonobese diabetic (NOD) islets. Shortly after 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 normoglycemia in all of 14 grafted mice for over 4 wk after transplantation. In contrast, NOD mice with IL-10-producing islet grafts became diabetic in all of six grafted mice within 2 wk af-ter transplantation. Reverse transcription-PCR analysis revealed that local production of IL-12p40 led to the decrease of interferon-gamma and the augmentation of transforming growth factor-beta at the graft site. These results suggest that IL-12 plays an important role in the destruction of islet cells at the inflamed site of autoimmunity. Such a local blockade of IL-12 would be a useful gene therapy for human autoimmune diabetes.
authors.affiliation: Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Nagata
authors.forename: K
authors.initials: K
authors.lastname: Arisawa
authors.forename: R
authors.initials: R
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Fujihira
authors.forename: N
authors.initials: N
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Moriyama
authors.forename: M
authors.initials: M
authors.lastname: Miki
authors.forename: I
authors.initials: I
authors.lastname: Saito
authors.forename: H
authors.initials: H
authors.lastname: Hamada
authors.forename: K
authors.initials: K
authors.lastname: Yokono
authors.forename: M
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000256:Adenoviridae; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006085:Graft Survival / Q000276:immunology; D007328:Insulin / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007668:Kidney / Q000601:surgery; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D007328:Insulin; D016753:Interleukin-10; D018664:Interleukin-12