Brain Injury Research Group, School of Biomedicine, University of Manchester, Manchester Academic Health Science Centre, Salford Royal Foundation Trust, Salford M6 8HD, UK.
Cytokine. 2012 Jun;58(3):384-9. doi: 10.1016/j.cyto.2012.02.016. Epub 2012 Mar 22.
Infections are common following stroke and adversely affect outcome. Cellular immune suppression associated with acute stroke may increase susceptibility to infection. Cytokines are important contributors to both stroke pathology and the response to infection. Since interleukin (IL)-1 blockade is a candidate treatment for cerebral ischemia, we examined whether administration of interleukin-1 receptor antagonist (IL-1Ra) to patients with acute stroke affected innate cellular immune responses in a phase II placebo-controlled trial.
Venous blood samples were taken prior to treatment initiation, at 24h and 5 to 7d. Blood was also drawn from stroke-free controls. Lipopolysaccharide (LPS) stimulation of whole-blood cultures assessed the potential of leukocytes to produce cytokines.
Induction of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-8 and IL-10 by LPS was significantly reduced in patients at admission, compared to controls. At 24h, cytokine induction remained suppressed in the placebo group. In contrast, for patients treated with IL-1Ra, induction of TNF-α, IL-6 and IL-10 was similar to controls and IL-1β induction was significantly greater than in the placebo group. At 5 to 7d, TNF-α and IL-1β induction remained suppressed only in the placebo group (p<0.05). Plasma cortisol concentrations, elevated at admission in patients compared to controls, were substantially reduced at 24h in the patients receiving IL-1Ra (p<0.05) and inversely correlated (p<0.001) with either TNF-α (r=-0.71) or IL-1β induction (r=-0.67) at admission.
Treatment with IL-1Ra reverses peripheral innate immune suppression in the acute phase of stroke, which is associated with attenuated cortisol production. The mechanisms underlying these observations, including the potential impact of IL-1Ra on stroke severity and the clinical significance of immune suppression, require further evaluation in larger studies.
中风后常发生感染，且感染对预后不利。与急性中风相关的细胞免疫抑制可能会增加感染的易感性。细胞因子是中风病理和感染反应的重要因素。由于白细胞介素 (IL)-1 阻断是治疗脑缺血的候选药物，我们在一项 II 期安慰剂对照试验中，研究了给予急性中风患者白细胞介素-1 受体拮抗剂 (IL-1Ra) 是否会影响固有细胞免疫反应。
在治疗开始前、24 小时和 5 至 7 天，采集静脉血样。也从无中风的对照组中抽取血液。通过脂多糖 (LPS) 刺激全血培养物来评估白细胞产生细胞因子的潜力。
与对照组相比，入院时患者的肿瘤坏死因子 (TNF)-α、IL-1β、IL-6、IL-8 和 IL-10 的 LPS 诱导明显降低。在 24 小时时，安慰剂组的细胞因子诱导仍受到抑制。相比之下，接受 IL-1Ra 治疗的患者，TNF-α、IL-6 和 IL-10 的诱导与对照组相似，而 IL-1β的诱导明显高于安慰剂组。在 5 至 7 天，仅在安慰剂组中 TNF-α和 IL-1β的诱导仍受到抑制（p<0.05）。与对照组相比，患者入院时的血浆皮质醇浓度升高，在接受 IL-1Ra 治疗的患者中，在 24 小时时显著降低（p<0.05），并且与 TNF-α（r=-0.71）或入院时的 IL-1β诱导（r=-0.67）呈负相关（p<0.001）。
IL-1Ra 治疗可逆转中风急性期的外周固有免疫抑制，这与皮质醇生成减少有关。这些观察结果的机制，包括 IL-1Ra 对中风严重程度的潜在影响以及免疫抑制的临床意义，需要在更大的研究中进一步评估。
