Therapeutic targeting of Syk in autoimmune diabetes.
Therapeutic targeting of Syk in autoimmune diabetes.
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DOI：
10.4049/jimmunol.1000983
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发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Clynes R
中科院分区：
文献类型：
--
作者：
Colonna L;Catalano G;Chew C;D'Agati V;Thomas JW;Wong FS;Schmitz J;Masuda ES;Reizis B;Tarakhovsky A;Clynes R
在APC中，蛋白酪氨酸激酶Syk是几种免疫受体（包括BCR和FcR）的信号传导所必需的。我们发现，树突状细胞（DC）中syk基因的条件性消融消除了RIP-mOVA小鼠中Fcγ R介导的致糖尿病T细胞的交叉致敏，这是用选择性Syk抑制剂R788处理的野生型RIP-mOVA小鼠中的一种表型。除了阻断Fcγ R介导的事件外，R788还阻断了BCR介导的Ag呈递，从而广泛中断了体液对T细胞驱动的自身免疫的贡献。事实上，口服R788显著延迟了NOD小鼠的自发性糖尿病发作，并成功延迟了早期糖尿病的进展，即使在葡萄糖耐受不良发生后开始治疗。在DC水平，R788治疗与胰岛素特异性CD 8启动减少和DC数量减少相关。在B细胞水平，R788降低总B细胞数量和总IG浓度。有趣的是，R788增加了产生IL-10的B细胞的数量，从而诱导了具有免疫调节活性的致耐受性B细胞群。总之，我们通过遗传学和药理学方法表明，APC中的Syk是T细胞介导的自身免疫性疾病（如1型糖尿病）的一个有吸引力的靶点。
In APCs, the protein tyrosine kinase Syk is required for signaling of several immunoreceptors, including the BCR and FcR. We show that conditional ablation of the syk gene in dendritic cells (DCs) abrogates FcγR-mediated cross priming of diabetogenic T cells in RIP-mOVA mice, a situation phenocopied in wild-type RIP-mOVA mice treated with the selective Syk inhibitor R788. In addition to blocking FcγR-mediated events, R788 also blocked BCR-mediated Ag presentation, thus broadly interrupting the humoral contributions to T cell-driven autoimmunity. Indeed, oral administration of R788 significantly delayed spontaneous diabetes onset in NOD mice and successfully delayed progression of early-established diabetes even when treatment was initiated after the development of glucose intolerance. At the DC level, R788 treatment was associated with reduced insulin-specific CD8 priming and decreased DC numbers. At the B cell level, R788 reduced total B cell numbers and total Ig concentrations. Interestingly, R788 increased the number of IL-10–producing B cells, thus inducing a tolerogenic B cell population with immunomodulatory activity. Taken together, we show by genetic and pharmacologic approaches that Syk in APCs is an attractive target in T cell-mediated autoimmune diseases such as type 1 diabetes.
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DOI：
10.4049/jimmunol.0803052
发表时间：
2009-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Blair PA;Chavez-Rueda KA;Evans JG;Shlomchik MJ;Eddaoudi A;Isenberg DA;Ehrenstein MR;Mauri C
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Mauri C
影响因子：
32.4
作者：
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通讯作者：
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影响因子：
15.9
作者：
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通讯作者：
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DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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通讯作者：
Reizis B
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.