Prevention of diabetes in NOD nice by administration of dendritic cells deficient in nuclear transcription factor-κB activity
Prevention of diabetes in NOD nice by administration of dendritic cells deficient in nuclear transcription factor-κB activity
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DOI：
10.2337/diabetes.52.8.1976
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发表时间：
2003-08-01
期刊：
影响因子：
7.7
通讯作者：
Lu, L
中科院分区：
文献类型：
--
作者：
Ma, LL;Qian, SG;Lu, L
在1型糖尿病患者和非肥胖糖尿病（NOD）小鼠中发现树突状细胞（DCs）异常与核转录因子(NF)- κ b活性增强有关。有利于免疫原性dc发展的不平衡可能易患该疾病，通过给药缺乏NF-kappaB活性的dc来恢复平衡可能预防糖尿病。我们在体外用NF-kappaB特异性寡脱氧核糖核苷酸（NF-kappaB ODN DC）治疗NOD小鼠骨髓培养的树突状细胞，评估其在体内预防糖尿病发展的效果。凝胶移位，DC核提取物测定证实NF-kappaB ODN特异性抑制NF-kappaB DNA结合。NF-kappaB ODN DC的共刺激分子表达、白细胞介素(IL)-12的产生以及呈递同种异体和胰岛相关抗原的免疫刺激能力均被显著抑制。nf - κ b ODN使DC抵抗脂多糖刺激。6-7周龄NOD小鼠注射2x106 NF-kappaB ODN dc可有效预防糖尿病的发生。NF-kappaB ODN dc处理的动物胰腺淋巴结的t细胞表现出对胰岛抗原的低反应性，干扰素- γ和IL-2的产生低。这些发现为自身免疫性糖尿病的机制提供了新的见解，并可能导致新的预防策略的发展。
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.