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 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.
Yasuda
H
H
Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan.
Nagata
M
M
Arisawa
K
K
Yoshida
R
R
Fujihira
K
K
Okamoto
N
N
Moriyama
H
H
Miki
M
M
Saito
I
I
Hamada
H
H
Yokono
K
K
Kasuga
M
M
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
D007328:Insulin; D016753:Interleukin-10; D018664:Interleukin-12