Granulocyte-macrophage colony stimulating factor in COVID-19: friend or foe?
Granulocyte-macrophage colony stimulating factor in COVID-19: friend or foe?
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DOI：
10.1016/s2665-9913(21)00078-3
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发表时间：
2021-06
期刊：
影响因子：
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通讯作者：
Dagna L
中科院分区：
文献类型：
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作者：
Mehta P;Chambers RC;Dagna L
COVID-19的双相模型现在已经得到了很好的建立，最初是病毒血症期，随后是宿主炎症过度期，在一个亚组的患者中，不适当的、过度的免疫反应与高死亡率相关，这可能对免疫调节治疗有反应。1随机对照试验（例如，RECOVERY和REMAP-CAP）显示了皮质类固醇2和白细胞介素（IL）-6阻断剂在降低重度COVID-19患者死亡率方面的疗效，尽管IL-6抑制剂的结果好坏参半。3粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种免疫调节细胞因子，由于其在导致单核细胞和巨噬细胞活化的促炎性高细胞因子血症和抗病毒免疫中的作用，它增加了COVID-19药物试验的复杂性和挑战性。GM-CSF的治疗性阻断和重组给药都有其合理性，4，5并且有越来越多的证据表明GM-CSF靶向治疗重度COVID-19患者。严重COVID-19患者的支气管肺泡灌洗液分析显示，克隆扩增的组织驻留记忆样Th 17细胞具有GM-CSF和IL-17 A细胞因子表达的潜在致病性特征;这些记忆样Th 17细胞被认为与肺巨噬细胞和细胞毒性CD 8 + T细胞相互作用，并与疾病严重程度和肺损伤相关。6. COVID-19患者血清中高GM-CSF蛋白浓度与更严重的临床病程相关。6此外，在安全性方面，抑制GM-CSF可能优于靶向IL-6，因为对C反应蛋白和发热的药效学抑制可能不太明显，这有助于检测继发感染。队列研究显示了靶向GM-CSF（lenzumab）7或其受体（mavrilimumab）8的药物的疗效信号，但迫切期待稳健的对照试验数据。
A biphasic model of COVID-19 is now well-established, with an initial viraemic phase, followed by a host hyperinflammatory phase in a subgroup of patients with an inappropriate, excessive immune response associated with high mortality, which might respond to immunomodulatory therapy. 1 Randomised controlled trials (eg, RECOVERY and REMAP-CAP) have shown the efficacy of corticosteroids2 and interleukin (IL)-6 blockade in reducing mortality in patients with severe COVID-19, although there have been mixed results with IL-6 inhibition. 3Granulocyte-macrophage colony stimulating factor (GM-CSF) is an immunoregulatory cytokine that exemplifies the complexity and challenges of drug trials in COVID-19, given its role in both the pro-inflammatory hyper cytokinaemia leading to monocyte and macrophage activation, and in antiviral immunity. There is rationale for both therapeutic blockade and recombinant administration of GM-CSF, 4, 5 and there is accumulating evidence for targeting GM-CSF in patients with severe COVID-19. Bronchoalveolar lavage fluid analysis from patients with severe COVID-19 has shown clonally expanded tissue-resident memory-like Th17 cells with a potentially pathogenic profile of cytokine expression of GM-CSF and IL-17A; these memory-like Th17 cells are thought to interact with lung macrophages and cytotoxic CD8+ T cells, and are associated with disease severity and lung damage. 6 High GM-CSF protein concentrations in the serum of patients with COVID-19 is associated with a more severe clinical course. 6 Additionally, inhibiting GM-CSF might have advantages over targeting IL-6 with respect to safety, because there might be less pronounced pharmacodynamic suppression of C-reactive protein and fever, which can facilitate the detection of secondary infection. Cohort studies have shown an efficacy signal for drugs targeting GM-CSF (lenzilumab) 7 or its receptor (mavrilimumab), 8 but robust controlled trial data have been eagerly anticipated.