Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice
Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice
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DOI：
10.4049/jimmunol.1501603
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发表时间：
2015-12-15
影响因子：
4.4
通讯作者：
Tsokos, George C.
中科院分区：
文献类型：
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作者：
Otomo, Kotaro;Koga, Tomohiro;Tsokos, George C.
自身免疫性疾病的治疗仍然主要基于使用全身作用的免疫抑制药物，这总是会导致严重的副作用。钙/钙调蛋白依赖性蛋白激酶 IV 参与 IL-2 的抑制和 IL-17 的产生。其药理学或遗传抑制可限制小鼠的自身免疫性疾病。在本研究中，我们证明 KN93 是一种钙/钙调蛋白依赖性蛋白激酶 IV 的小分子抑制剂，通过纳米脂质凝胶递送系统靶向 CD4(+) T 细胞，可显着减少实验性自身免疫性脑脊髓炎，并且在狼疮小鼠模型中比全身递送的游离药物效力强 10 倍。 KN93 的靶向递送不会耗尽 T 细胞，但可以有效阻断 Th17 细胞的分化和扩增，分别在患有实验性自身免疫性脑脊髓炎或狼疮的小鼠的脊髓和肾脏中进行测量。这些结果凸显了对参与自身免疫发病机制的分子进行细胞靶向抑制作为推进自身免疫性疾病治疗的一种手段的前景。
Treatment of autoimmune diseases is still largely based on the use of systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV is involved in the suppression of IL-2 and the production of IL-17. Its pharmacologic or genetic inhibition limits autoimmune disease in mice. In this study, we demonstrate that KN93, a small-molecule inhibitor of calcium/calmodulin-dependent protein kinase IV, targeted to CD4(+) T cells via a nanolipogel delivery system, markedly reduced experimental autoimmune encephalomyelitis and was 10-fold more potent than the free systemically delivered drug in the lupus mouse models. The targeted delivery of KN93 did not deplete T cells but effectively blocked Th17 cell differentiation and expansion as measured in the spinal cords and kidneys of mice developing experimental autoimmune encephalomyelitis or lupus, respectively. These results highlight the promise of cell-targeted inhibition of molecules involved in the pathogenesis of autoimmunity as a means of advancing the treatment of autoimmune diseases.