Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats.
Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats.
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DOI：
10.3389/fimmu.2021.699987
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发表时间：
2021
影响因子：
7.3
通讯作者：
van Duivenvoorde LM
中科院分区：
文献类型：
--
作者：
van Tok MN;Mandour M;Wahle J;Labadia ME;van de Sande MGH;Nabozny G;Baeten DL;van Duivenvoorde LM
IL-17A在脊柱关节炎(SpA)的发病机制中起重要作用。在这里，我们评估了抑制RAR相关的孤儿受体-γ(RORC)，控制IL-17产生的关键转录因子，对HLAB27转基因(TG)大鼠实验性SpA的影响。用热灭活结核分枝杆菌免疫HLAB27TG大鼠，建立实验性SpA模型。免疫后第7天、第14天和第21天获得的脾细胞在体外重新刺激，以评估促炎症细胞因子的诱导。然后用RORC抑制剂对大鼠进行预防性治疗，而不是使用药物作为对照。通过引流淋巴结中促炎症细胞因子的表达来评价RORC抑制的生物学效应。临床监测关节炎和脊柱炎，组织学证实周围和轴向炎症、破坏和新骨形成的程度。体外信使核糖核酸和蛋白质分析显示，在诱导人类白细胞抗原B27TG大鼠发病时，多种淋巴细胞亚群可以快速和选择性地诱导产生IL-17A和IL-22。体内预防性抑制RORC可抑制IL-17A、IL-17F和IL-22的表达，而不影响其他T辅助细胞亚群相关基因的表达。这种生物学效应并未转化为临床疗效，因为抑制RORC显著加速了关节炎和脊柱炎的发生，并加重了关节炎的临床严重程度。实验性SpA的这种恶化得到了炎症、破坏和新骨形成增加的组织病理学证实。尽管显著抑制了IL-17轴，但RORC抑制剂治疗加速并加重了在人类白细胞抗原B27TG大鼠模型中的实验性SpA。
IL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats. Experimental SpA was induced by immunization of HLA-B27 tg rats with heat-inactivated Mycobacterium tuberculosis. Splenocytes obtained at day 7, 14 and 21 after immunization were restimulated ex vivo to assess the induction of pro-inflammatory cytokines. Rats were then prophylactically treated with a RORC inhibitor versus vehicle control. The biologic effect of RORC inhibition was assessed by pro-inflammatory cytokine expression in draining lymph nodes. Arthritis and spondylitis were monitored clinically, and the degree of peripheral and axial inflammation, destruction and new bone formation was confirmed by histology. Ex vivo mRNA and protein analyses revealed the rapid and selective induction of IL-17A and IL-22 production by a variety of lymphocyte subsets upon disease induction in HLA-B27 tg rats. Prophylactic RORC inhibition in vivo suppressed the expression of IL-17A, IL17F, and IL-22 without affecting the expression of other T helper cell subset related genes. This biological effect did not translate into clinical efficacy as RORC inhibition significantly accelerated the onset of arthritis and spondylitis, and aggravated the clinical severity of arthritis. This worsening of experimental SpA was confirmed by histopathological demonstration of increased inflammation, destruction, and new bone formation. Despite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model.
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影响因子：
27.4
作者：
Baeten D;Østergaard M;Wei JC;Sieper J;Järvinen P;Tam LS;Salvarani C;Kim TH;Solinger A;Datsenko Y;Pamulapati C;Visvanathan S;Hall DB;Aslanyan S;Scholl P;Padula SJ
通讯作者：
Padula SJ
影响因子：
158.5
作者：
Baeten, Dominique;Sieper, Joachim;Richards, Hanno B.
通讯作者：
Richards, Hanno B.
影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
168.9
作者：
Baeten, Dominique;Baraliakos, Xenofon;Hueber, Wolfgang
通讯作者：
Hueber, Wolfgang
ixekizumab，一种白介素17a特异性单克隆抗体，用于治疗活性银屑病性关节炎的生物学患者：由24周的随机，双盲，安慰剂对照和活性（Adalimumab）的24周随机，III阶段（Adalimumab）的结果。试验精神-P1。
影响因子：
27.4
作者：
Mease PJ;van der Heijde D;Ritchlin CT;Okada M;Cuchacovich RS;Shuler CL;Lin CY;Braun DK;Lee CH;Gladman DD;SPIRIT-P1 Study Group
通讯作者：
SPIRIT-P1 Study Group