title: Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally transduced with immunomodulating molecules.
abstract: Pancreatic islet transplantation has the potential to maintain normoglycemia in patients with established type 1 diabetes, thereby obviating the need for frequent insulin injections. Our previous study showed that recombinant IL-12p40-producing islets prevented the recurrence of NOD diabetes. First, to see which immunomodulating molecule-secreting islet grafts can most powerfully prevent diabetes development in NOD mice without immunosuppressant, NOD islets were transfected with one of the following adenoviral vectors: Ad.IL-12p40, Ad.TGF-beta, Ad.CTLA4-Ig, or Ad.TNF-alpha after which they were transplanted under the renal capsule of acutely diabetic NOD mice. The immunomodulating molecules produced by these adenovirus-transfected islets in vitro were 74+/-19ng, 50+/-4ng, 821+/-31ng, and 77+/-18ng/100 islets, respectively. Transplantation of IL-12p40, TNF-alpha, and CTLA4-Ig but not TGF-beta-secreting islets displayed enhanced survival and delayed diabetes recurrence in recent-onset diabetic recipients. IL-12p40-producing islet grafts most powerfully prevented recurrent diabetes in NOD mice. In addition, local production of TNF-alpha and CTLA4-Ig significantly prolonged islet graft survival. In second series of experiment, these manipulated islets were transplanted under the renal capsule of 10-week-old NOD recipients and were also transplanted subcutaneously into 2-week-old NOD recipients. Transplantation of these islets into 2- or 10-week-old pre-diabetic mice failed to protect them from developing diabetes; in fact, transplantation of Ad.TNF-alpha-transfected islets into 2-week-old mice actually accelerated diabetes onset. Taken together, this approach was ineffectual as a prophylactic protocol. In conclusion, this study showed comparisons of the immunomodulating effects of 4 different adenoviral vectors in the same transplantation model and local production of IL-12p40, TNF-alpha and CTLA4-Ig significantly prevented recurrent diabetes in NOD mice.
authors.affiliation: Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Sakata
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Reiko
authors.initials: R
authors.lastname: Kotani
authors.forename: Midori
authors.initials: M
authors.lastname: Kurohara
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Okumachi
authors.forename: Minoru
authors.initials: M
authors.lastname: Kishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Arai
authors.forename: Kenta
authors.initials: K
authors.lastname: Hara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokono
authors.forename: Masao
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D012008:Recurrence; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha