Prevention of diabetes in NOD nice by administration of dendritic cells deficient in nuclear transcription factor-κB activity

被引:73
作者
Ma, LL
Qian, SG
Liang, XY
Wang, LF
Woodward, JE
Giannoukakis, N
Robbins, PD
Bertera, S
Trucco, M
Fung, JJ
Lu, L
机构
[1] Univ Pittsburgh, Med Ctr, Thomas E Starzl Transplantat Inst, Dept Surg, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Pathol, Inst Diabet, Pittsburgh, PA 15261 USA
[3] Univ Pittsburgh, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA
[4] Childrens Hosp Pittsburgh, Div Immunogenet, Pittsburgh, PA 15213 USA
关键词
D O I
10.2337/diabetes.52.8.1976
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Abnormalities of dendritic Cells (DCs) have been identified in type 1 diabetic patients and in nonobese diabetic (NOD) mice that are associated with augmented nuclear transcription factor (NF)-kappaB activity. An imbalance that favors development of the immunogenic DCs may predispose to the disease, and restoration of the balance by administration of DCs deficient in NF-kappaB activity may prevent diabetes., DCs propagated from NOD mouse bone marrow and treated with NF-kappaB-specific oligodeoxyribonucleotide (ODN) in vitro (NF-kappaB ODN DC) were assessed for efficacy in prevention of diabetes development in vivo. Gel shift,assay with DC nuclear extracts confirmed specific inhibition of NF-kappaB DNA binding by NF-kappaB ODN. The costimulatory molecule expression, interleukin (IL)-12 production, and immunostimulatory capacity in presenting allo- and islet-associated antigens by NF-kappaB ODN DC were significantly suppressed. NF-kappaB ODN renders DC resistant to lipopolysaccharide stimulation. Administration of 2 X 106 NF-kappaB ODN DCs into NOD mice aged 6-7 weeks effectively prevented the onset of diabetes. T-cells from pancreatic lymph nodes of NF-kappaB ODN DC-treated animals exhibited hyporesponsiveness to islet antigens with low production of interferon-gamma and IL-2. These findings provide novel insights into the mechanisms of autoimmune diabetes and may lead to development of novel preventive strategies.
引用
收藏
页码:1976 / 1985
页数:10
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