Fiala Milan, Mizwicki Mathew T, Weitzman Rachel, Magpantay Larry, Nishimoto Norihiro
Department of Surgery, David Geffen School of Medicine at UCLA 100 UCLA Medical Plaza, Suite 220, Los Angeles, CA 90095-6970, USA.
Am J Neurodegener Dis. 2013 Jun 21;2(2):129-39. Print 2013.
Patients with sporadic amyotrophic lateral sclerosis (sALS) show inflammation in the spinal cord and peripheral blood. The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1 (SOD1) through caspase1, interleukin 1 (IL1), IL6 and chemokine signaling. Inflammatory gene activation is inhibited in vitro by tocilizumab, a humanized antibody to IL6 receptor (IL6R). Tocilizumab inhibits global interleukin-6 (IL6) signaling, a key mechanism in chronic rheumatoid disorders. Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells (PBMCs) of 10 sALS patients, and the effects of tocilizumab (Actemra(R)) infusions. At baseline, one half of ALS subjects had strong inflammatory activation (Group 1) (8 genes up regulated >4-fold, P<0.05 vs. controls) and the other half (Group 2) had weak activation. All patients showed greater than four-fold up regulation of MMP1, CCL7, CCL13 and CCL24. Tocilizumab infusions in the Group 1 patients resulted in down regulation of inflammatory genes (in particular IL1β), whereas in the Group 2 patients in up regulation of inflammatory genes. Post-infusion serum and CSF concentrations of tocilizumab inhibited caspase1 activation in vitro. Three of 5 patients receiving tocilizumab infusions showed time-limited attenuation of clinical progression. In conclusion, inflammation of sALS patients at baseline is up- or down-regulated in comparison to controls, but is partially normalized by tocilizumab infusions.
散发性肌萎缩侧索硬化症（sALS）患者的脊髓和外周血存在炎症。这种炎症是由聚集的超氧化物歧化酶1（SOD1）通过半胱天冬酶1、白细胞介素1（IL1）、IL6和趋化因子信号刺激巨噬细胞所驱动。在体外，托珠单抗（一种抗IL6受体（IL6R）的人源化抗体）可抑制炎症基因的激活。托珠单抗可抑制整体白细胞介素-6（IL6）信号传导，这是慢性类风湿性疾病的关键机制。在此，我们研究了10例sALS患者外周血单核细胞（PBMCs）的体内基线炎症基因转录情况，以及托珠单抗（雅美罗®）输注的效果。在基线时，一半的ALS受试者具有强烈的炎症激活（第1组）（8个基因上调>4倍，与对照组相比P<0.05），另一半（第2组）具有较弱的激活。所有患者的基质金属蛋白酶1（MMP1）、CC趋化因子配体7（CCL7）、CCL13和CCL24均有超过四倍的上调。第1组患者输注托珠单抗导致炎症基因下调（特别是IL1β），而第2组患者则导致炎症基因上调。输注后血清和脑脊液中的托珠单抗浓度在体外可抑制半胱天冬酶1的激活。5例接受托珠单抗输注的患者中有3例临床进展出现了限时性缓解。总之，与对照组相比，sALS患者基线时的炎症上调或下调，但托珠单抗输注可使其部分恢复正常。
