In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes.
In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes.
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DOI：
10.1084/jem.20082481
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发表时间：
2009-05-11
期刊：
影响因子：
--
通讯作者：
Jung T
中科院分区：
文献类型：
--
作者：
Lachmann HJ;Lowe P;Felix SD;Rordorf C;Leslie K;Madhoo S;Wittkowski H;Bek S;Hartmann N;Bosset S;Hawkins PN;Jung T
白细胞介素1β（IL-1β）在人血浆中几乎检测不到，这一事实阻碍了对IL-1 β在人类炎症性疾病中的研究。我们证明，通过将抗人IL-1β抗体卡那单抗（ACZ 885）给予人体，IL-1β-抗体复合物的形成允许检测体内产生的IL-1β。生成了一个二室数学模型，预测健康受试者中6 ng/d IL-1β的组成性产生率。相比之下，cryopyrin-associated periodic syndrome（CAPS）患者，一种罕见的单基因疾病，由不受控制的caspase-1活性和IL-1产生驱动，产生的平均值为31 ng/d。Canakinumab治疗不仅诱导了长期的完全临床应答，而且在治疗8周内将IL-1β的产生率降低至正常水平，表明这些患者中的IL-1β产生主要是IL-1β驱动的。该模型进一步表明，IL-1β是驱动疾病严重程度和对卡那单抗的反应持续时间的唯一细胞因子。不需要对天然IL-1拮抗剂进行校正以拟合数据。总之，该研究为人类IL-1β的产生和调节提供了新的见解。它还表明CAPS完全由IL-1β介导，并且canakinumab治疗恢复了生理性IL-1β的产生。
The investigation of interleukin 1β (IL-1β) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti–human IL-1β antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1β–antibody complexes allowed the detection of in vivo–produced IL-1β. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1β in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1β to normal levels within 8 wk of treatment, suggesting that IL-1β production in these patients was mainly IL-1β driven. The model further indicated that IL-1β is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1β in man. It also indicated that CAPS is entirely mediated by IL-1β and that canakinumab treatment restores physiological IL-1β production.
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作者：
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