Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis
Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis
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DOI：
10.1073/pnas.0601335103
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发表时间：
2006-04-11
影响因子：
11.1
通讯作者：
Martin, R
中科院分区：
文献类型：
--
作者：
Bielekova, B;Catalfamo, M;Martin, R
给予Daclizumab，一种针对IL-2R阿尔法链的人源化mAb，可以显著减少多发性硬化症患者的脑部炎症。在这里，我们表明，达利珠单抗治疗只导致轻微的功能阻断的CD4(+)T细胞，主要候选的多发性硬化症的发病机制。相反，Daclizumab治疗与循环中CD4(+)和CD8(+)T细胞的逐渐下降以及体内CD56(明亮的)自然杀伤(INK)细胞的显著扩张有关，并且这种效应与治疗反应高度相关。体外研究表明，NK细胞通过接触依赖机制抑制激活的外周血单核细胞培养中T细胞的存活。个体患者体内CD56(Bright)NK细胞的扩增与CD4(+)、CD8(+)T细胞数量的收缩呈正相关，为Daclizumab治疗过程中NK细胞介导的活化T细胞的负性免疫调节提供了证据。我们的数据支持存在一种免疫调节途径，其中激活的CD56(Bright)NK细胞抑制T细胞的存活。这种免疫调节对于自身免疫性疾病的治疗和移植排斥反应的治疗以及肿瘤免疫的修饰具有潜在的重要意义。
Administration of daclizumab, a humanized mAb directed against the IL-2R alpha chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4(+) T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4(+) and CD8(+) T cells and significant expansion of CD56(bright) natural killer (INK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56(bright) NK cells and contraction of CD4(+) and CD8(+) T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56(bright) NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.