Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner
Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner
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DOI：
10.4049/jimmunol.179.11.7225
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Delovitch, Terry L.
中科院分区：
文献类型：
--
作者：
Hussain, Shabbir;Delovitch, Terry L.
尽管B细胞在NOD小鼠1型糖尿病（T1 D）的起始中起致病作用，但尚不清楚活化的I1细胞是否能够维持耐受性并转移对T1 D的保护。在这项研究中，我们证明，静脉输注BCR刺激的NOD脾B细胞到NOD小鼠在5-6周龄开始既延迟发作，降低T1 D的发病率，而在9周龄开始的治疗只延迟T1 D的发作。这种BCR活化的B细胞诱导的T1 D保护需要B细胞产生IL-10，因为从NOD小鼠输注活化的B细胞。IL-10（-/-）小鼠不能提供T1 D保护。与此结果一致，在输注IL-10（-/-）BCR刺激的B细胞的NOD受体的胰岛中观察到严重的胰岛炎，但在输注BCR刺激的NOD B细胞的NOD受体的胰岛中未观察到。输注活化NOD B细胞的治疗效果与观察到的胰岛炎症减少、IFN-γ产生减少以及来自BCR刺激的NOD B细胞的NOD受体的脾细胞和CD 4（+）T细胞相对于来自PBS处理的对照NOD小鼠的脾细胞和CD 4（+）T细胞的IL-4和IL-10产生增加密切相关。我们的数据表明，输注BCR刺激的B细胞可以维持长期耐受性，并通过IL-10依赖性机制保护NOD小鼠免受T1 D的影响，并提高了静脉输注自体产生IL-10的BCR激活的B细胞在治疗上用于保护有T1 D风险的人类受试者的可能性
Although B cells play a pathogenic role in the initiation of type 1 diabetes (T1D) in NOD mice, it is not known whether activated 11 cells can maintain tolerance and transfer protection from T1D. In this study, we demonstrate that i.v. transfusion of BCR-stimulated NOD spleen B cells into NOD mice starting at 5-6 wk of age both delays onset and reduces the incidence of T1D, whereas treatment initiated at 9 wk of age only delays onset of T1D. This BCR-activated B cell-induced protection from T1D requires IL-10 production by B cells, as transfusion of activated B cells from NOD.IL-10(-/-) mice does not confer protection from T1D. Consistent with this result, severe insulitis was observed in the islets of NOD recipients of transfused NOD.IL-10(-/-) BCR-stimulated B cells but not in the islets of NOD recipients of transfused BCR-stimulated NOD B cells. The therapeutic effect of transfused activated NOD B cells correlates closely with the observed decreased islet inflammation, reduced IFN-gamma production and increased production of IL-4 and IL-10 by splenocytes and CD4(+) T cells from NOD recipients of BCR-stimulated NOD B cells relative to splenocytes and CD4(+) T cells from PBS-treated control NOD mice. Our data demonstrate that transfused BCR-stimulated B cells can maintain long-term tolerance and protect NOD mice from T1D by an IL-10-dependent mechanism, and raise the possibility that i.v. transfusion of autologous IL-10-producing BCR-activated B cells may be used therapeutically to protect human subjects at risk for T1D