Prevention of recurrent but not spontaneous autoimmune diabetes by transplanted NOD islets adenovirally Transduced with immunomodulating molecules

被引：6

作者：

Sakata, Muneaki ^{[1
]}

Yasuda, Hisafumi ^{[1
]}

Moriyama, Hiroaki ^{[1
]}

Yamada, Katsumi ^{[1
]}

Kotani, Reiko ^{[1
]}

Kurohara, Midori ^{[1
]}

Okumachi, Yasuyo ^{[1
]}

Kishi, Minoru ^{[1
]}

Arai, Takashi ^{[1
]}

Hara, Kenta ^{[1
]}

Hamada, Hirofumi ^{[2
]}

Yokono, Koichi ^{[1
]}

Nagata, Masao ^{[1
]}

机构：

[1] Kobe Univ, Grad Sch Med, Dept Internal & Geriatr Med, Chuo Ku, Kobe, Hyogo 6500017, Japan

[2] Sapporo Med Univ, Dept Mol Med, Chuo Ku, Sapporo, Hokkaido 0608556, Japan

来源：

DIABETES RESEARCH AND CLINICAL PRACTICE | 2008年 / 80卷 / 03期

关键词：

autoimmune diabetes; immunomodulating molecule; islet transplantation; adenoviral vector; TNF-alpha;

D O I：

10.1016/j.diabres.2008.01.030

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 +/- 19 ng, 50 +/- 4 ng, 821 +/- 31 ng, and 77 +/- 18 ng/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. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

引用

页码：352 / 359

页数：8

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