GM-CSF in murine psoriasiform dermatitis: Redundant and pathogenic roles uncovered by antibody-induced neutralization and genetic deficiency.
GM-CSF in murine psoriasiform dermatitis: Redundant and pathogenic roles uncovered by antibody-induced neutralization and genetic deficiency.
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DOI：
10.1371/journal.pone.0182646
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Burkhardt H
中科院分区：
文献类型：
--
作者：
Scholz T;Weigert A;Brüne B;Sadik CD;Böhm B;Burkhardt H
粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种多效性的Th 17衍生的细胞因子，被认为在多种自身免疫性疾病（包括类风湿性关节炎和银屑病）的发病机制中起关键作用。用阻断GM-CSF活性的单克隆抗体治疗类风湿性关节炎患者与良好的治疗效果相关。我们评估了GM-CSF作为银屑病治疗干预的潜在靶点的作用，使用组合的药理学和遗传学方法和咪喹莫特诱导的银屑病样皮炎（IMQPD）的小鼠模型。通过抗GM-CSF抗体中和鼠GM-CSF改善IMQPD。相反，GM-CSF的遗传缺陷并不改变IMQPD的病程，这表明存在对慢性而非急性GM-CSF缺乏的补偿机制。进一步的研究发现了在缺乏GM-CSF的情况下IMQPD的替代致病途径，其特征在于浆细胞样树突状细胞群扩增以及IFNα和IL-22的释放。在短期抗GM-CSF治疗期间，野生型小鼠中该途径未被激活。我们的研究支持GM-CSF作为银屑病治疗靶点的潜在价值。然而，在永久缺乏GM-CSF的情况下发现银屑病样皮炎的替代致病途径，表明需要在长期GM-CSF阻断的治疗使用期间进行监测。
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade.
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MOR103，一种对粒细胞巨噬细胞刺激因子的人类单克隆抗体，用于治疗中等类风湿关节炎患者：IB/IIA期随机，双盲，安慰剂对照，剂量 - 剂量 - 降低试验的结果。
影响因子：
27.4
作者：
Behrens F;Tak PP;Østergaard M;Stoilov R;Wiland P;Huizinga TW;Berenfus VY;Vladeva S;Rech J;Rubbert-Roth A;Korkosz M;Rekalov D;Zupanets IA;Ejbjerg BJ;Geiseler J;Fresenius J;Korolkiewicz RP;Schottelius AJ;Burkhardt H
通讯作者：
Burkhardt H
影响因子：
30.5
作者：
Duhen, Thomas;Geiger, Rebekka;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
6.5
作者：
Croxford, Andrew L.;Karbach, Susanne;Waisman, Ari
通讯作者：
Waisman, Ari
浆细胞样树突状细胞在刺激系统性自身免疫中的主要作用。
影响因子：
7.3
作者：
Huang X;Dorta-Estremera S;Yao Y;Shen N;Cao W
通讯作者：
Cao W
影响因子：
20.3
作者：
Li, Haiyan S.;Yang, Cliff Y.;Watowich, Stephanie S.
通讯作者：
Watowich, Stephanie S.