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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Therapeutic activity of an interleukin-4/interleukin-13 dual antagonist on oxazolone-induced colitis in mice
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Therapeutic activity of an interleukin-4/interleukin-13 dual antagonist on oxazolone-induced colitis in mice

机译：白介素4 /白介素13双重拮抗剂对恶唑酮诱发的小鼠结肠炎的治疗作用

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Interleukin-4 (IL-4) and IL-13 are critical drivers of immune activation and inflammation in ulcerative colitis, asthma and other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We have recently described a bifunctional therapeutic targeting IL-4 and IL-13 developed on a novel protein scaffold, generated by combining specific binding domains in an optimal configuration using appropriate linker regions. In the current study, the bifunctional IL-4/IL-13 antagonist was evaluated in the murine oxazoloneinduced colitis model, which produces disease with features of ulcerative colitis. The bifunctional IL-4/IL-13 antagonist reduced body weight loss throughout the 7-day course of the model, and ameliorated the increased colon weight and decreased colon length that accompany disease. Colon tissue gene expression was modulated in accordance with the treatment effect. Concentrations of serum amyloid P were elevated in proportion to disease severity, making it an effective biomarker. Serum concentrations of the bifunctional IL-4/IL-13 antagonist were inversely proportional to disease severity, colon tissue expression of pro-inflammatory genes, and serum amyloid P concentration. Taken together, these results define a panel of biomarkers signifying engagement of the IL-4/IL-13 pathway, confirm the T helper type 2 nature of disease in this model, and demonstrate the effectiveness of dual cytokine blockade.
机译：白细胞介素-4（IL-4）和IL-13是溃疡性结肠炎，哮喘和其他疾病中免疫激活和炎症的关键驱动因素。因为这些细胞因子可能具有冗余功能，所以双重靶向有望实现更高的疗效。我们最近描述了一种在新型蛋白支架上开发的靶向IL-4和IL-13的双功能治疗药物，该蛋白支架是通过使用适当的接头区域以最佳构型结合特异性结合域而产生的。在当前的研究中，在鼠恶唑酮诱导的结肠炎模型中评估了双功能IL-4 / IL-13拮抗剂，该模型产生具有溃疡性结肠炎特征的疾病。双功能IL-4 / IL-13拮抗剂在模型的整个7天疗程中减少了体重减轻，并改善了伴随疾病的结肠重量增加和结肠长度减少。根据治疗效果调节结肠组织基因表达。血清淀粉样蛋白P的浓度与疾病的严重程度成正比，使其成为有效的生物标志物。双功能IL-4 / IL-13拮抗剂的血清浓度与疾病的严重程度，促炎基因的结肠组织表达以及血清淀粉样蛋白P浓度成反比。综上所述，这些结果确定了一系列标志着IL-4 / IL-13通路参与的生物标志物，证实了该模型中2型T辅助性疾病的性质，并证明了双重细胞因子阻断的有效性。

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