Ma Linlin, Qian Shiguang, Liang Xiaoyan, Wang Lianfu, Woodward Jennifer E, Giannoukakis Nick, Robbins Paul D, Bertera Suzanne, Trucco Massimo, Fung John J, Lu Lina
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Diabetes. 2003 Aug;52(8):1976-85. doi: 10.2337/diabetes.52.8.1976.
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 DCs resistant to lipopolysaccharide stimulation. Administration of 2 x 10(6) 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.
在1型糖尿病患者和非肥胖糖尿病（NOD）小鼠中已发现树突状细胞（DC）异常，这与核转录因子（NF）-κB活性增强有关。有利于免疫原性DC发育的失衡可能使个体易患该疾病，通过给予NF-κB活性缺陷的DC来恢复平衡可能预防糖尿病。评估了从NOD小鼠骨髓中培养并在体外用NF-κB特异性寡脱氧核糖核苷酸（ODN）处理的DC（NF-κB ODN DC）在体内预防糖尿病发生的效果。用DC核提取物进行的凝胶迁移试验证实了NF-κB ODN对NF-κB DNA结合的特异性抑制。NF-κB ODN DC的共刺激分子表达、白细胞介素（IL）-12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-κB ODN使DC对脂多糖刺激具有抗性。向6-7周龄的NOD小鼠注射2×10⁶个NF-κB ODN DC可有效预防糖尿病的发生。来自NF-κB ODN DC处理动物胰腺淋巴结的T细胞对胰岛抗原反应低下，干扰素-γ和IL-2产生量低。这些发现为自身免疫性糖尿病的发病机制提供了新见解，并可能导致新预防策略的开发。
