Reich Kristian, Papp Kim A, Matheson Robert T, Tu John H, Bissonnette Robert, Bourcier Marc, Gratton David, Kunynetz Rodion A, Poulin Yves, Rosoph Les A, Stingl Georg, Bauer Wolfgang M, Salter Janeen M, Falk Thomas M, Blödorn-Schlicht Norbert A, Hueber Wolfgang, Sommer Ulrike, Schumacher Martin M, Peters Thomas, Kriehuber Ernst, Lee David M, Wieczorek Grazyna A, Kolbinger Frank, Bleul Conrad C
Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
Probity Medical Research Inc, Waterloo, ON, Canada.
Exp Dermatol. 2015 Jul;24(7):529-35. doi: 10.1111/exd.12710. Epub 2015 May 8.
The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.
银屑病对靶向白细胞介素（IL）-23/IL-17A通路的抗体的反应表明，17型辅助性T细胞（Th17细胞）在该疾病中起重要作用。在一项2期试验中，我们研究了100例中重度银屑病患者接受3种不同静脉给药方案的抗IL-17A抗体司库奇尤单抗（第1天1×3mg/kg或1×10mg/kg，或第1、15和29天3×10mg/kg）或安慰剂后的临床和免疫反应模式。基线活检显示了活动性银屑病的典型特征，包括中性粒细胞在表皮积聚以及超过60%的病例中形成微脓肿。中性粒细胞是含有IL-17的浸润细胞中数量最多的部分，并且可能预先储存了这种细胞因子，因为从活动性斑块中分离出的中性粒细胞中未检测到IL-17A mRNA。单次输注后2周观察到司库奇尤单抗有显著临床反应，同时皮肤中性粒细胞大量清除，这与角质形成细胞异常的正常化以及IL-17诱导的中性粒细胞趋化因子（如CXCL1、CXCL8）的减少平行；对T细胞和CD11c阳性树突状细胞数量的影响出现得更晚。组织学和免疫学改善通常呈剂量依赖性，在安慰剂组中未观察到。在最低剂量组中，一些受试者在第12周出现中性粒细胞复发；这些受试者比没有微脓肿的受试者复发更快。我们的研究结果表明银屑病中存在中性粒细胞-角质形成细胞轴，可能涉及中性粒细胞衍生的IL-17，并且是司库奇尤单抗等IL-17A导向疗法的早期靶点。
