Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis.
Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis.
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DOI：
10.1371/journal.pone.0052208
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Berberich-Siebelt F
中科院分区：
文献类型：
--
作者：
Benkert TF;Dietz L;Hartmann EM;Leich E;Rosenwald A;Serfling E;Buttmann M;Berberich-Siebelt F
那他珠单抗是一种针对整合素α-4（CD 49 d）的重组单克隆抗体。它被批准用于治疗多发性硬化症（MS）患者，多发性硬化症是一种CNS慢性炎症性自身免疫性疾病。虽然那他珠单抗治疗显示出较高的疗效，但已将其与进行性多灶性白质脑病（PML）作为严重不良反应联系起来。此外，停药有时会引起病因不明的疾病活动反弹。在这里，我们研究了这种粘附阻断抗体与T淋巴细胞的结合是否可以通过直接诱导细胞内信号传导事件来调节其表型。分析了来自健康供体并在体外用那他珠单抗治疗或来自接受第一剂那他珠单抗的MS患者的原代CD 4 + T淋巴细胞。Natalizumab诱导从健康供体离体增殖的活化原代人CD 4 + T细胞中IL-2、IFN-γ和IL-17表达轻度上调，这与对淋巴因子表达的促炎共刺激作用一致。沿着这一点，那他珠单抗结合触发快速MAPK/ERK磷酸化。此外，它在几小时内降低效应细胞上的CD 49 d表面表达。持续的CD 49 d下调可能归因于整合素的内化和降解。重要的是，一些接受首剂那他珠单抗治疗的MS患者的CD 4 + T细胞在输注后24小时就产生了更多的IL-2、IFN-γ和IL-17。总之，这些数据表明，除了其粘附阻断作用模式外，那他珠单抗还具有轻度直接信号传导能力，这可以支持外周血T淋巴细胞的促炎表型。这可能解释了为什么在停止那他珠单抗治疗后，在一些MS患者中观察到疾病活动反弹或IRIS。
Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-γ and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-γ and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation.
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