1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization
1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization
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DOI：
10.1073/pnas.1306072110
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发表时间：
2013-12-24
影响因子：
11.1
通讯作者：
Gocke, Anne R.
中科院分区：
文献类型：
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作者：
Grishkan, Inna V.;Fairchild, Amanda N.;Gocke, Anne R.
辅助性T细胞（T-H）运输的药理学靶向为改善自身免疫性疾病如多发性硬化（MS）提供了有吸引力的机会。MS风险与维生素D缺乏有关，其生物活性形式1，25-二羟基维生素D3 [1，25（OH）（2）D-3]已被证明可通过不完全理解的机制预防实验性自身免疫性脑脊髓炎（MS的小鼠模型）。在此，我们系统地研究了1，25（OH）（2）D-3对T-H细胞从淋巴结向CNS迁移过程中的作用。我们的数据表明，髓鞘反应性T-H细胞在1，25（OH）（2）D-3的存在下成功产生，分泌促炎细胞因子，并且不优先分化为抑制性T细胞。这些细胞能够离开淋巴结，进入外周循环，并迁移到s。C.免疫接种点。然而，来自1，25（OH）（2）D-3处理的小鼠的TH细胞不能进入CNS实质，而是维持在外周。在治疗停止后，小鼠迅速发展为实验性自身免疫性脑脊髓炎，表明1，25（OH）（2）D-3仅通过阻止T-H细胞迁移到CNS而暂时预防该疾病。
Pharmacologic targeting of T helper (T-H) cell trafficking poses an attractive opportunity for amelioration of autoimmune diseases such as multiple sclerosis (MS). MS risk is associated with vitamin D deficiency, and its bioactive form, 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D-3], has been shown to prevent experimental autoimmune encephalomyelitis, a mouse model of MS, via an incompletely understood mechanism. Herein, we systematically examined 1,25(OH)(2)D-3 effects on T-H cells during their migration from the lymph nodes to the CNS. Our data demonstrate that myelin-reactive T-H cells are successfully generated in the presence of 1,25(OH)(2)D-3, secrete proinflammatory cytokines, and do not preferentially differentiate into suppressor T cells. These cells are able to leave the lymph node, enter the peripheral circulation, and migrate to the s. c. immunization sites. However, TH cells from 1,25(OH)(2)D-3-treated mice are unable to enter the CNS parenchyma but are instead maintained in the periphery. Upon treatment cessation, mice rapidly develop experimental autoimmune encephalomyelitis, demonstrating that 1,25(OH)(2)D-3 prevents the disease only temporarily likely by halting T-H cell migration into the CNS.