Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation
Immune Suppression via Glucocorticoid-Stimulated Monocytes: A Novel Mechanism To Cope with Inflammation
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DOI：
10.4049/jimmunol.1300891
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发表时间：
2014-08-01
影响因子：
4.4
通讯作者：
Sunderkoetter, Cord
中科院分区：
文献类型：
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作者：
Varga, Georg;Ehrchen, Jan;Sunderkoetter, Cord
糖皮质激素(GC)被用作广泛抑制炎症(如过敏或自身免疫性疾病)的一线治疗药物，但其长期使用受到严重副作用的限制。我们以前的工作表明，GCs在单核细胞中诱导了稳定的抗炎表型，我们利用GC刺激的单核细胞(GCsms)来实现GC介导的靶向治疗效果。我们证明了GCSM与T细胞相互作用，在体外抑制CD8(+)T细胞的增殖，特别是CD4(+)T细胞的细胞因子的释放，并支持Foxp3(+)细胞的产生。因此，我们在体内检测了它们在CD4(+)T细胞诱导的结肠炎中的免疫抑制作用。我们发现，给患有严重结肠炎的小鼠注射GCSM可以消除炎症，并在几天内导致显著的临床改善。从GCsM治疗的小鼠中恢复的T细胞显示，促炎症细胞因子干扰素-γ和IL-17的分泌减少。此外，在结肠局部炎症部位可检测到Foxp3(+)CD4(+)T细胞群。因此，GCsms能够在体外和体内改变T细胞反应，以及下调和临床治疗严重的T细胞介导性结肠炎。
Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti-inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release of CD8(+) and, especially, CD4(+) T cells in vitro, and that they support generation of Foxp3(+) cells. Therefore, we tested their immunosuppressive potential in CD4(+) T cell-induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-gamma and IL-17. Furthermore, clusters of Foxp3(+) CD4(+) T cells were detectable at local sites of inflammation in the colon. Thus, GCsMs are able to modify T cell responses in vitro and in vivo, as well as to downregulate and clinically cure severe T cell-mediated colitis.