Flt3-ligand treatment prevents diabetes in NOD mice
Flt3-ligand treatment prevents diabetes in NOD mice
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DOI：
10.2337/diabetes.53.8.1995
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发表时间：
2004-08-01
期刊：
影响因子：
7.7
通讯作者：
Ildstad, ST
中科院分区：
文献类型：
--
作者：
Chilton, PM;Rezzoug, F;Ildstad, ST
混合嵌合体逆转1型糖尿病自身免疫的机制尚未明确。NOD小鼠在骨髓祖细胞的产生方面具有充分表征的缺陷，据信这对自身免疫过程有显著贡献。因此，我们研究了嵌合体是否会引起这种缺陷的纠正。混合嵌合体使NOD小鼠骨髓祖细胞的产生恢复到正常水平。值得注意的是，NOD骨髓细胞以及供体骨髓细胞产生成熟的髓系后代，供体嵌合体的水平与缺损的恢复程度无关。此外，与Flt 3-配体一起培养的NOD骨髓细胞产生了主要由成熟骨髓树突状细胞组成的热稳定抗原阳性/Ly 6C（+）群体，这表明潜在的异常不是细胞内在的，而是由于成熟骨髓后代（包括骨髓树突状细胞）发育受阻。值得注意的是，用Flt 3-配体治疗NOD小鼠显著降低了胰岛炎和糖尿病的进展，并与髓样树突状细胞的显著增加和胰腺淋巴结中CD 4（+）/CD 25（+）细胞的体内诱导相关。因此，Flt 3-配体治疗和/或在前驱糖尿病候选者中建立混合嵌合体可以提供治疗糖尿病的良性和新颖的方法。
The mechanism by which mixed chimerism reverses autoimmunity in type 1 diabetes has not been defined. NOD mice have a well-characterized defect in the production of myeloid progenitors that is believed to contribute significantly to the autoimmune process. We therefore investigated whether chimerism induces a correction of this defect. Mixed chimerism restored production of myeloid progenitors in NOD mice to normal levels. Notably, NOD bone marrow cells as well as donor bone marrow cells produced the mature myeloid progeny, and the level of donor chimerism was not correlated with the degree of restoration of the defect. Moreover, NOD bone marrow cells cultured with Flt3-ligand developed a heat-stable antigen-positive/Ly6C(+) population comprised primarily of mature myeloid dendritic cells, suggesting that the underlying abnormality is not cell intrinsic but rather due to a block in development of mature myeloid progeny, including myeloid dendritic cells. Strikingly, treatment of NOD mice with Flt3-ligand significantly decreased insulitis and progression to diabetes and was associated with a significant increase in myeloid dendritic cells and in vivo induction of CD4(+)/CD25(+) cells in the pancreatic lymph node. Therefore, Flt3-ligand treatment and/or the establishment of mixed chimerism in prediabetic candidates may provide a benign and novel approach to treat diabetes.